EP1453512B1 - Acetylene derivatives having mglur 5 antagonistic activity - Google Patents

Acetylene derivatives having mglur 5 antagonistic activity Download PDF

Info

Publication number
EP1453512B1
EP1453512B1 EP02792867A EP02792867A EP1453512B1 EP 1453512 B1 EP1453512 B1 EP 1453512B1 EP 02792867 A EP02792867 A EP 02792867A EP 02792867 A EP02792867 A EP 02792867A EP 1453512 B1 EP1453512 B1 EP 1453512B1
Authority
EP
European Patent Office
Prior art keywords
hydroxy
phenylethynyl
octahydro
carboxylic acid
ethyl ester
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP02792867A
Other languages
German (de)
French (fr)
Other versions
EP1453512B8 (en
EP1453512A1 (en
Inventor
Fabrizio Gasparini
Yves Auberson
Silvio Ofner
Terance W. Hart
Kaspar Zimmermann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
Original Assignee
Novartis AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=9926969&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=EP1453512(B1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Novartis AG filed Critical Novartis AG
Priority to SI200230385T priority Critical patent/SI1453512T1/en
Publication of EP1453512A1 publication Critical patent/EP1453512A1/en
Application granted granted Critical
Publication of EP1453512B1 publication Critical patent/EP1453512B1/en
Publication of EP1453512B8 publication Critical patent/EP1453512B8/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/23—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/08—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms with acylated ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel acetylene derivatives, their preparation, their use as pharmaceuticals and pharmaceutical compositions containing them.
  • WO 99/02497 describes pyridine derivatives useful for treating disorders mediated by mGluR5.
  • US 4 129 658 discloses certain compounds falling within the scope of formula I, for use as synthetic intermediates.
  • the compounds may exist in optically active form or in form of mixtures of optical isomers, e.g. in form of racemic mixtures. All optical isomers and their mixtures including the racemic mixtures are part of the present invention.
  • reaction of process a) can be effected according to conventional methods, e.g. as described in Examples I (step e), 2 (step d), 5 (step b) and 8.
  • process b) leads to a mixture of a compound of formula I wherein A forms a single bond with X and a compound of formula I wherein A forms a single bond with Y, which are subsequently separated according to conventional methods, e.g. as described in Examples 6, 9 and 10.
  • a so obtained compound of formula I can be converted into another compound of formula I according to conventional methods, e.g. as described in Examples I (steps f and g), 4 and 7.
  • Acid addition salts may be produced from the free bases in known manner, and vice versa.
  • Resulting acid addition salts can be converted into other acid addition salts or into the free bases in a manner known per se.
  • the compounds of formula I may also be obtained in the form of hydrates or may include the solvent used for crystallization.
  • the compounds of formula I exhibit a marked and selective modulating, especially antagonistic, action at human metabotropic glutamate receptors (mGluRs).
  • mGluRs human metabotropic glutamate receptors
  • This can be determined in vitro for example at recombinant human metabotropic glutamate receptors, especially PLC-coupled subtypes thereof such as mGluR5, using different procedures like, for example, measurement of the inhibition of the agonist induced elevation of intracellular Ca 2+ concentration in accordance with L. P. Daggett et al., Neuropharm. Vol. 34, pages 871-886 (1995), P. J. Flor et al., J. Neurochem. Vol.
  • the compounds of formula I are therefore useful in the treatment of disorders associated with irregularities of the glutamatergic signal transmission, and of nervous system disorders mediated full or in part by mGluR5.
  • disorders associated with irregularities of the glutamatergic signal transmission are for example epilepsy, cerebral ischemias, especially acute ischemias, ischemic diseases of the eye, muscle spasms such as local or general spasticity and, in particular, convulsions or pain.
  • Nervous system disorders mediated full or in part by mGluR5 are for example acute, traumatic and chronic degenerative processes of the nervous system, such as Parkinson's disease, senile dementia, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis and multiple sclerosis, psychiatric diseases such as schizophrenia and anxiety, depression, pain, itch and drug abuse, e.g. alcohol and nicotine abuse and cocaine use disorders.
  • the agents of the invention show reversal of Freund complete adjuvant (FCA) induced hyperalgesia [cf. J. Donnerer et al., Neuroscience 49 , 693-698 (1992) and C.J. Woolf, Neuroscience 62, 327-331 (1994)].
  • FCA Freund complete adjuvant
  • the appropriate dosage will of course vary depending upon, for example, the compound employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained at a daily dosage of from about 0.5 to about 100 mg/kg animal body weight. In larger mammals, for example humans, an indicated daily dosage is in the range from about 5 to 1500 mg, preferably about 10 to about 1000 mg of the compound conveniently administered in divided doses up to 4 times a day or in sustained release form.
  • the present invention provides compounds of formula I for use as pharmaceuticals, e.g. in the treatment of disorders associated with irregularities of the glutamatergic signal transmission, and of nervous system disorders mediated full or in part by mGluR5.
  • the invention also provides the use of a compound of formula I, in the treatment of disorders associated with irregularities of the glutamatergic signal transmission, and of nervous system disorders mediated full or in part by mGluR5.
  • the invention provides the use of compound of formula I for the manufacture of a pharmaceutical composition designed for the treatment of disorders associated with irregularities of the glutamatergic signal transmission, and of nervous system disorders mediated full or in part by mGluR5.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I in association with at least one pharmaceutical carrier or diluent.
  • compositions for enteral such as nasal, rectal or oral, or parenteral, such as intramuscular or intravenous, administration to warm-blooded animals (human beings and animals) that comprise an effective dose of the pharmacological active ingredient alone or together with a significant amount of a pharmaceutically acceptable carrier.
  • the dose of the active ingredient depends on the species of warm-blooded animal, body weight, age and individual condition, individual pharmacokinetic data, the disease to be treated and the mode of administration.
  • compositions comprise from approximately 1% to approximately 95%, preferably from approximately 20% to approximately 90%, active ingredient.
  • Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, dragées, tablets or capsules.
  • the compound of formula I may alternatively be administered e.g. topically in the form of a cream, gel or the like, or by inhalation, e.g. in dry powder form.
  • compositions comprising compound of formula I include, e.g. a solid dispersion, an aqueous solution, e.g. containing a solubilising agent, a microemulsion and a suspension of an agent of the invention.
  • the composition may be buffered to a pH in the range of e.g. from 3.5 to 9.5, by a suitable buffer.
  • compositions of the present invention are prepared in a manner known per se, for example by means of conventional dissolving, lyophilizing, mixing, granulating or confectioning processes.
  • the compound of formula I can be administered either alone, or in combination with other pharmaceutical agents effective in the treatment of conditions mentioned above.
  • the compound of formula I can be used in combination with analgesic agents (opiates) or with non-steroidal anti-inflammatory drugs (NSAIDs) such as Rofecoxib (Vioxx® ), Celecoxib (Celebrex® ) or Lumiracoxib (Prexige® ).
  • analgesic agents opiates
  • NSAIDs non-steroidal anti-inflammatory drugs
  • Rofecoxib Rofecoxib
  • Celecoxib Celecoxib
  • Lumiracoxib Prexige®
  • the compound of formula I can be used in combination with bupropione (Zyban® ).
  • the preferred compound of formula I includes the (-)-(3aR, 4S, 7aR)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester in free base or pharmaceutically acceptable acid addition salt form.
  • Said compound inhibits the quisqualate-induced inositol phosphate turnover in hmGlu5 expressing cells with an IC 50 concentration of 30 nM.
  • a stress-induced hyperthermia of 0.92 ⁇ 0.09°C was reduced to 0.56 ⁇ 0.06° C at 0.1 mg/kg p.o., to 0.42 ⁇ 0.06° C at 1 mg/kg p.o. and to 0.18 ⁇ 0.05° C at 10 mg/kg p.o. (p ⁇ 0.001 in each case).
  • Example 1a (-)-(3aR,4S,7aR)-4-Hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid ethyl ester
  • Example 1b (-)-(3aR,4S,7aR)-Furan-2-yl-(4-hydroxy-4-m-tolylethynyl-octahydro-indol-1-yl)-methanone
  • Example 1c ( ⁇ )-(3aRS,4SR,7aRS)-4-(3-Chlorophenylethynyl)-4-hydroxy-octahydro-indole-1-carboxylic acid ethyl ester
  • Example 1d ( ⁇ )-(3aRS,4SR,7aRS)-4-(3-Fluoro-phenylethynyl)-4-hydroxy-octahydro-indole-1-carboxylic acid ethyl ester
  • Example 1e (3aRS,4SR,7aRS)-4-Hydroxy-4-phenylethynyl-octahydro-indole-1-carboxylic acid(S)(tetrahydrofuran-3-yl)ester
  • Example 1f (3aRS,4SR,7aRS)-4-Hydroxy-4-phenylethynyl-octahydro-indole-1-carboxylic acid(R)(tetrahydrofuran-3-yl)ester
  • Example 1g (3aRS,4SR,7aRS)-4-Hydroxy-4-(3-chlorophenylethynyl)-octahydro-indol-1-carboxylic acid-(S)(tetrahydrofuran-3yl)ester
  • Example 1h ( ⁇ )-(3aRS,4SR,7aRS)-4-Hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid ethyl ester
  • Example 1i ( ⁇ )-(3aRS,4SR,7aRS)-4-(4-Fluoro-phenylethynyl)-4-hydroxy-octahydro-indole-1-carboxylic acid ethyl ester
  • Example 1i ( ⁇ )-(3aRS,4SR,7aRS)-4-(3-chlorophenylethynyl)-4-hydroxy-1-methanesulfonyl-octahydro-indole
  • Example 2 ( ⁇ )-(3aRS,7aRS)-4-Phenylethynyl-2,3,3a,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester and ( ⁇ )-(RS)-4-phenylethynyl-2,3,5,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester
  • Example 2a ( ⁇ )-(3RS,7aRS)-2,2,2-Trifluoro-1-(4-phenylethynyl-2,3,3a,6,7,7a-hexahydro-indol-1-yl)-ethanone
  • Example 2b ( ⁇ )-(RS)-4- m -Tolylethynyl-2,3,5,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester
  • Example 2c ( ⁇ )-(3RS,7aRS)-4- m -Tolylethynyl-2,3,3a,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester
  • Example 2d ( ⁇ )-(3RS,7aRS)-4-(4-Chloro-phenylethynyl)-2,3,3a,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester
  • Example 2e ( ⁇ )-(3RS,7aRS)-4-(2-Fluoro-phenylethynyl)-2,3,3a,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester
  • Example 2f ( ⁇ )-(3RS,7aRS)-4-(3-Fluoro-phenylethynyl)-2,3,3a,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester
  • Example 2i ( ⁇ )-(RS)-4.-(3-Methoxy-phenylethynyl)-2,3,5,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester
  • Example 3a ( ⁇ )-(3aRS,4RS,7aSR)-4-Hydroxy-4-m-tolylethynyl-octahydro-isoindole-2-carboxylic acid ethyl ester
  • Example 3b ( ⁇ )-(3aRS,4RS,7aSR)-4-Hydroxy-4-p-tolylethynyl-octahydro-isoindole-2-carboxylic acid ethyl ester
  • Example 3c ( ⁇ )-(3aRS,4RS,7aSR)-4-(3-Cyano-phenylethynyl)-4-hydroxy-octahydroisoindole-2-carboxylic acid ethyl ester
  • Example 3d ( ⁇ )-(3aRS,4RS,7aSR)-4-Hydroxy-4-(3-methoxy-phenylethynyl)-octahydroisoindole-2-carboxylic acid ethyl ester
  • Example 3e ( ⁇ )-(3aRS,4RS,7aSR)-4-(3-Fluoro-phenylethynyl)-4-hydroxy-octahydroisoindole-2-carboxylic acid ethyl ester
  • Example 4a ( ⁇ )-(3aRS,4RS,7aSR)-4-Hydroxy-4-m-tolylethynyl-octahydro-isoindole-2-carboxylic acid tert -butyl ester
  • Example 5a ( ⁇ )-(3aRS,4RS,7aSR)-Furan-2-yl-(4-hydroxy-4-m-tolylethynyl-octahydroisoindol-2-yl)-methanone
  • Example 5b ( ⁇ )-(3aRS,4RS,7aSR)-Cyclopropyl-(4-hydroxy-4-m-tolylethynyl-octahydroisoindol-2-yl)-methanone
  • Example 5c ( ⁇ )-(3aRS,4RS,7aSR)- (4-Hydroxy-4-m-tolylethynyl-octahydro-isoindol-2-yl)-pyridin-3-yl-methanone
  • Example 6 ( ⁇ )-((1SR,3SR)-3-Hydroxy-3- m -tolylethynyl-cyclohexyl)-methyl-carbamic acid methyl ester and ( ⁇ )-((1RS,3SR)-3-hydroxy-3- m -tolylethynyl-cyclohexyl)-methyl-carbamic acid methyl ester
  • Example 6a ( ⁇ )-(1RS,3SR)-((3-Hydroxy-3- m -tolylethynyl-cyclohexyl)-(4-methoxy-benzyl)-carbamic acid ethyl ester.
  • Example 6b ( ⁇ )-(1RS,3RS)-((3-Hydroxy-3- m -tolylethynyl-cyclohexyl)-(4-methoxy-benzyl)-carbamic acid ethyl ester.
  • Example 6c ( ⁇ )-[(1RS,3SR)-3-Hydroxy-3-(3-methoxy-phenylethynyl)-5,5-dimethylcyclohexyl]-methyl-carbamic acid methyl ester.
  • Example 6d ( ⁇ )-(1RS,3SR)-(3-Hydroxy-5,5-dimethyl-3- m -tolylethynyl-cyclohexyl)-methyl-carbamic acid methyl ester.
  • Example 6e ( ⁇ )-[(1RS,3SR)-3-(3-Fluoro-phenylethynyl)-3-hydroxy-5,5-dimethyl-cyclohexyl]-methyl-carbamic acid methyl ester
  • Example 6f ( ⁇ )-[(1RS,3RS)-3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-methyl-carbamic acid methyl ester.
  • Example 6g ( ⁇ )-[(1RS,3SR)-3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-methyl-carbamic acid methyl ester.
  • Example 6h ( ⁇ )-[(1RS,3RS)-3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexy]-methyl-carbamic acid methyl ester.
  • Example 6i ( ⁇ )-[(1RS,3SR)-3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-methyl-carbamic acid methyl ester.
  • Example 6i ( ⁇ )-[(1RS,3RS)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-methyl-carbamic acid methyl ester.
  • Example 6k ( ⁇ )-[(1 RS,3SR)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-methyl-carbamic acid methyl ester.
  • Example 6g ( ⁇ )-(1RS,3SR)-[3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbamic acid ethyl ester
  • Example 6aa ( ⁇ )-(1RS,3SR)-(3-Hydroxy-3-m-tolylethynyl-cyclohexyl)-carbamic acid tert-butyl ester
  • Example 6ab ( ⁇ )-(1RS,3RS)-(3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbamic acid tert-butyl ester
  • Example 6ac ( ⁇ )-(1RS,3SR)-(3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbamic acid tert-butyl ester
  • Example 6ad ( ⁇ )-(1RS,3RS)-[3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbamic acid methyl ester
  • Example 6ae ( ⁇ )-(1RS,3SR)-[3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbamic acid methyl ester
  • Example 7 ( ⁇ )-(3-Phenylethynyl-cyclohex-2-enyl)-carbamic acid ethyl ester and ( ⁇ )-3-phenylethynyl-cyclohex-3-enyl)-carbamic acid ethyl ester
  • Example 9a ( ⁇ )-[(4aRS,5SR,8aSR)-5-(3-Chloro-phenylethynyl)-5-hydroxy-octahydro-quinolin-1-yl]-furan-2-yl-methanone
  • Example 9b ( ⁇ )-[(4aRS,5RS,8aSR)-5-(3-Chloro-phenylethynyl)-5-hydroxy-octahydro-quinolin-1-yl]-furan-2-yl-methanone
  • Example 9c ( ⁇ )-(4aRS,5RS,8aSR)-5-(3-Chloro-phenylethynyl)-5-hydroxy-octahydroquinoline-1-carboxylic acid tert-butyl ester
  • Example 9e ( ⁇ )-[(4aRS,5SR,8aSR)-5-(3-chloro-phenylethynyl)-5-hydroxy-octahydro-quinolin-1-yl]-(4-methyl-piperazin-1-yl)-methanone
  • Example 10 ( ⁇ )-(4aRS,5RS,8aSR)-5-(3-chloro-phenylethynyl)-5-hydroxy-octahydroquinoline-1-carboxylic acid ethyl ester and ( ⁇ )-(4aRS,5SR,8aSR)- 5-(3-chloro-phenylethynyl)-5-hydroxy-octahydro-quinoline-1-carboxylic acid ethyl ester
  • Example 10a ( ⁇ )-(4aRS,5SR,8aSR)-5-Hydroxy-5-m-tolylethynyl-octahydro-guinoline-1-carboxylic acid ethyl ester
  • Example 10b ( ⁇ )-(4aRS,5RS,8aSR)-5-Hydroxy-5-m-tolylethynyl-octahydro-quinoline-1-carboxylic acid ethyl ester
  • Example 11 ( ⁇ )-Ethyl-((1SR,3SR)-3-hydroxy-3-m-tolylethynyl-cyclopentyl)-carbamic acid methyl ester and ( ⁇ )-ethyl-((1SR,3RS-3-hydroxy-3-m-tolylethynyl-cyclopentyl)-carbamic acid methyl ester

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Addiction (AREA)
  • Pain & Pain Management (AREA)
  • Psychology (AREA)
  • Rheumatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Indole Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Quinoline Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

The invention provides compounds of formula (I) wherein m, n, A, R, R', R', Ro, X and Y are as defined in the description, and their preparation. The compounds of formula (I) are useful as pharmaceuticals in the treatment of e.g. nervous system disorders.

Description

  • The present invention relates to novel acetylene derivatives, their preparation, their use as pharmaceuticals and pharmaceutical compositions containing them.
  • More particularly the invention provides a compound of formula I
    Figure imgb0001
     wherein
    • m
    is 0 or 1,
    n
    is 0 or 1 and
    A
    is hydroxy
    X
    is hydrogen and
    Y
    is hydrogen, or
    A
    forms a single bond with X or with Y;
    R0
    is hydrogen, (C1-4)alkyl, (C1-4)alkoxy, trifluoromethyl, halogen, cyano, nitro, -COOR1 wherein R1 is (C1-4)alkyl or -COR2 wherein R2 is hydrogen or (C1-4)alkyl, and
    R
    is -COR3, -COOR3, -CONR4R5 or -SO2R6, wherein R3 is (C1-4)alkyl, (C3-7)cycloalkyl or optionally substituted phenyl, 2-pyridyl or 2-thienyl, R4 and R5, independently, are hydrogen or (C1-4)alkyl and R6 is (C1-4)alkyl, (C3-7)cycloalkyl or optionally substituted phenyl,
    R'
    is hydrogen or (C1-4)alkyl and
    R"
    is hydrogen or (C1-4)alkyl, or
    R' and R"
    together form a group -CH2-(CH2)p-
    wherein p is 0, 1 or 2, in which case one of n and p is different from 0, with the proviso that R0 is different from hydrogen, trifluoromethyl and methoxy when m is 1,
    n is 0, A is hydroxy, X and Y are both hydrogen, R is COOEt and R' and R" together form a group -(CH2)2-,
    in free base or acid addition salt form, for use as a pharmaceutical.
  • WO 99/02497 describes pyridine derivatives useful for treating disorders mediated by mGluR5. US 4 129 658 discloses certain compounds falling within the scope of formula I, for use as synthetic intermediates.
  • On account of the asymmetrical carbon atoms present in the compounds of formula I and their salts, the compounds may exist in optically active form or in form of mixtures of optical isomers, e.g. in form of racemic mixtures. All optical isomers and their mixtures including the racemic mixtures are part of the present invention.
  • The compounds of formula I and their salts may be prepared as follows:
    • a) for the production of a compound of formula I wherein A is hydroxy, reacting a compound of formula II
      Figure imgb0002
       wherein m, n, R, R' and R" are as defined above, with a compound of formula III
      Figure imgb0003
       wherein R0 is as defined above, or
    • b) for the production of a compound of formula I wherein A forms a single bond with X or with Y, dehydrating a compound of formula I wherein A is hydroxy,
    and recovering the resulting compound of formula I in free base or acid addition salt form.
  • The reaction of process a) can be effected according to conventional methods, e.g. as described in Examples I (step e), 2 (step d), 5 (step b) and 8.
  • The dehydration of process b) leads to a mixture of a compound of formula I wherein A forms a single bond with X and a compound of formula I wherein A forms a single bond with Y, which are subsequently separated according to conventional methods, e.g. as described in Examples 6, 9 and 10.
  • A so obtained compound of formula I can be converted into another compound of formula I according to conventional methods, e.g. as described in Examples I (steps f and g), 4 and 7.
  • Working up the reaction mixtures according to the above processes and purification of the compounds thus obtained may be carried out in accordance to known procedures.
  • Acid addition salts may be produced from the free bases in known manner, and vice versa.
  • Compounds of formula I in optically pure form can be obtained from the corresponding racemates according to well-known procedures. Alternatively, optically pure starting materials can be used.
  • The starting materials of formulae II and III are known or may be obtained from known compounds, using conventional procedures.
  • Compounds of formula I obtained in accordance with the above-described process can be converted into other compounds of formula I in customary manner.
  • Resulting acid addition salts can be converted into other acid addition salts or into the free bases in a manner known per se.
  • The compounds of formula I, including their acid addition salts, may also be obtained in the form of hydrates or may include the solvent used for crystallization.
  • Compounds of formula I and their pharmaceutically acceptable acid addition salts, exhibit valuable pharmacological properties and are therefore useful as pharmaceuticals.
  • In particular, the compounds of formula I exhibit a marked and selective modulating, especially antagonistic, action at human metabotropic glutamate receptors (mGluRs). This can be determined in vitro for example at recombinant human metabotropic glutamate receptors, especially PLC-coupled subtypes thereof such as mGluR5, using different procedures like, for example, measurement of the inhibition of the agonist induced elevation of intracellular Ca2+ concentration in accordance with L. P. Daggett et al., Neuropharm. Vol. 34, pages 871-886 (1995), P. J. Flor et al., J. Neurochem. Vol. 67, pages 58-63 (1996) or by determination to what extent the agonist induced elevation of the inositol phosphate turnover is inhibited as described by T. Knoepfel et al., Eur. J. Pharmacol. Vol. 288, pages 389-392 (1994), L. P. Daggett et al., Neuropharm. Vol. 67, pages 58-63 (1996) and references cited therein. Isolation and expression of human mGluR subtypes are described in US-Patent No. 5,521,297. Selected agents of the invention show IC50 values for the inhibition of the quisqualate-induced inositol phosphate turnover, measured in recombinant cells expressing hmGluR5a of about 1 nM to about 50µM.
  • The compounds of formule I are therefore useful in the treatment of disorders associated with irregularities of the glutamatergic signal transmission, and of nervous system disorders mediated full or in part by mGluR5.
  • Disorders associated with irregularities of the glutamatergic signal transmission are for example epilepsy, cerebral ischemias, especially acute ischemias, ischemic diseases of the eye, muscle spasms such as local or general spasticity and, in particular, convulsions or pain.
  • Nervous system disorders mediated full or in part by mGluR5 are for example acute, traumatic and chronic degenerative processes of the nervous system, such as Parkinson's disease, senile dementia, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis and multiple sclerosis, psychiatric diseases such as schizophrenia and anxiety, depression, pain, itch and drug abuse, e.g. alcohol and nicotine abuse and cocaine use disorders.
  • The usefulness of the compounds of formula I in the treatment of the above-mentioned disorders can be confirmed in a range of standard tests including those indicated below:
  • Activity of the compounds of formula I in anxiety can be demonstrated in standard models such as the stress-induced hyperthermia in mice [cf. A. Lecci et al., Psychopharmacol. 101, 255-261]. At doses of about 0.1 to about 30 mg/kg p.o., the agents of the invention reverse the stress-induced hyperthermia.
  • At doses of about 4 to about 50 mg/kg p.o., the agents of the invention show reversal of Freund complete adjuvant (FCA) induced hyperalgesia [cf. J. Donnerer et al., Neuroscience 49, 693-698 (1992) and C.J. Woolf, Neuroscience 62, 327-331 (1994)].
  • For all the above mentioned indications, the appropriate dosage will of course vary depending upon, for example, the compound employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained at a daily dosage of from about 0.5 to about 100 mg/kg animal body weight. In larger mammals, for example humans, an indicated daily dosage is in the range from about 5 to 1500 mg, preferably about 10 to about 1000 mg of the compound conveniently administered in divided doses up to 4 times a day or in sustained release form.
  • In accordance with the foregoing, the present invention provides compounds of formula I for use as pharmaceuticals, e.g. in the treatment of disorders associated with irregularities of the glutamatergic signal transmission, and of nervous system disorders mediated full or in part by mGluR5.
  • The invention also provides the use of a compound of formula I, in the treatment of disorders associated with irregularities of the glutamatergic signal transmission, and of nervous system disorders mediated full or in part by mGluR5.
  • Furthermore the invention provides the use of compound of formula I for the manufacture of a pharmaceutical composition designed for the treatment of disorders associated with irregularities of the glutamatergic signal transmission, and of nervous system disorders mediated full or in part by mGluR5.
  • Moreover the invention relates to a pharmaceutical composition comprising a compound of formula I in association with at least one pharmaceutical carrier or diluent.
  • The pharmaceutical compositions according to the invention are compositions for enteral, such as nasal, rectal or oral, or parenteral, such as intramuscular or intravenous, administration to warm-blooded animals (human beings and animals) that comprise an effective dose of the pharmacological active ingredient alone or together with a significant amount of a pharmaceutically acceptable carrier. The dose of the active ingredient depends on the species of warm-blooded animal, body weight, age and individual condition, individual pharmacokinetic data, the disease to be treated and the mode of administration.
  • The pharmaceutical compositions comprise from approximately 1% to approximately 95%, preferably from approximately 20% to approximately 90%, active ingredient. Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, dragées, tablets or capsules.
  • The compound of formula I may alternatively be administered e.g. topically in the form of a cream, gel or the like, or by inhalation, e.g. in dry powder form.
  • Examples for compositions comprising compound of formula I include, e.g. a solid dispersion, an aqueous solution, e.g. containing a solubilising agent, a microemulsion and a suspension of an agent of the invention. The composition may be buffered to a pH in the range of e.g. from 3.5 to 9.5, by a suitable buffer.
  • The pharmaceutical compositions of the present invention are prepared in a manner known per se, for example by means of conventional dissolving, lyophilizing, mixing, granulating or confectioning processes.
  • The compound of formula I can be administered either alone, or in combination with other pharmaceutical agents effective in the treatment of conditions mentioned above.
  • For the indication pain, the compound of formula I can be used in combination with analgesic agents (opiates) or with non-steroidal anti-inflammatory drugs (NSAIDs) such as Rofecoxib (Vioxx® ), Celecoxib (Celebrex® ) or Lumiracoxib (Prexige® ).
  • For the indication nicotine use disorders, the compound of formula I can be used in combination with bupropione (Zyban® ).
  • The preferred compound of formula I includes the (-)-(3aR, 4S, 7aR)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester in free base or pharmaceutically acceptable acid addition salt form.
  • Said compound inhibits the quisqualate-induced inositol phosphate turnover in hmGlu5 expressing cells with an IC50 concentration of 30 nM. With the same compound, a stress-induced hyperthermia of 0.92 ± 0.09°C was reduced to 0.56 ± 0.06° C at 0.1 mg/kg p.o., to 0.42 ± 0.06° C at 1 mg/kg p.o. and to 0.18 ± 0.05° C at 10 mg/kg p.o. (p < 0.001 in each case).
  • The following non-limiting Examples illustrate the invention.
    • Example 1: (-)-(3aR,4S,7aR)-4-Hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester
    • a) 1,5,6,7-Tetrahydro-indol-4-one (38.4 g, 28.1 mmol), di-tert-butyldicarbonate (66 g; 302 mmol) and potassium tert-butylate (6 g; 62.5 mmol) in 1 I tetrahydrofuran are heated under reflux for 2 h. After cooling at room temperature the reaction mixture is poured on brine (1 l) and extracted with tert.-butylmethylether (4 X 500 ml). The combined organic phases are dried over Na2SO4, filtered and evaporated in vacuo. 51 g of yellowish oil are isolated and purified by column chromatography on silica gel (600 g; eluent hexane/ethylacetate 8:2 v/v). 30.5 g (92 %) of 1,5,6,7-Tetrahydro-indol-4-one-1-carboxylic acid tert.butyl ester as white crystals are isolated (mp 84-86°C).
    • b) 1,5,6,7-Tetrahydro-indol-4-one-1-carboxylic acid tert-butyl ester (60 g; 255 mmol) and 15 g of 5% Pt on charcoal (given in three portions of 5 g each; 24h, 48, 72h) in 1 l of methanol are hydrogenated (1 bar) at room temperature under stirring for 92 h. The mixture is filtered and the solvent evaporated in vacuo. The residual brownish oil is purified by chromatography on silica gel to yield (3aRS,4SR,7aRS)-4-hydroxyoctahydro-indole-1-carboxylic acid tert-butyl ester as a yellowish oil (41.3 g; yield = 67 %).
    • c) To a solution of oxalylchloride (1.54 ml; 17.6 mmol) in THF (320 ml) cooled to -60°C a solution of DMSO (2.28 ml; 32 mmol) in THF (32 ml) is added dropwise under stirring. After 5 min a solution of (3aRS,4SR,7aRS)-4-hydroxy-octahydro-indole-1-carboxylic acid tert-butyl ester (3.96 g; 16.4 mmol) in THF (64 ml) is added and the reaction mixture stirred for 100 min at -60°C. Triethylamine (11.2 ml; 80 mmol) is added and the cooling bath removed and the reaction mixture stirred for further 60 min. The reaction mixture is diluted with ethylacetate (1 l) and washed with sat. NaHCO3 (150 ml). The water phase is extracted with ethylacetate (300 ml). The combined organic phases are dried over Na2SO4, filtered and evaporated in vacuo. The residue is purified by column chromatography on silica gel (150 g) and the fractions containing the desired compound are collected and evaporated in vacuo to yield (3aRS,7aRS)-4-Oxo-octahydro-indole-1-carboxylic acid tert-butyl ester (2.51 g; yield = 65 %).
    • d1) 4 g of (3aRS,7aRS)-4-oxo-octahydro-indole-1-carboxylic acid tert-butyl ester are dissolved in 200 ml of hexane-ethanol 80:20 (v/v). This solution is injected via the pump on a 5 cm by 50 cm Chiralpak AD column (Daicel Chemical Industries). The chromatography is achieved at room temperature at a flow-rate of 100 ml/min and UV detection is performed at 210 nm. The mobile phase consists of a mixture of hexane-ethanol 80:20 (v/v). Under the applied chromatographic conditions, the (+)-enantiomer is isolated from a first fraction collected between 11 and 18 min, and the (-)-enantiomer from a second fraction collected between 20 and 40 min. After 6 injections of a total of 27 g of racemate, the fractions containing the corresponding enantiomers are combined to yield 12.55 g of (+)-enantiomer and 12.23 g of (-)-enantiomer, with an enantiomeric purity of 99% and 99.9%, respectively. The enantiomeric purity is determined on an analytical Chiralpak AD column (0.4 x 25 cm); mobile phase, hexane-ethanol 90:10 (v/v). (-)-(3aR,7aRr4-oxo-octahydro-indole-1-carboxylic acid tert-butyl ester ([α]D= -111.6); - (+)-(3aS,7aS)-4-oxo-octahydro-indole-1-carboxylic acid tert-butyl ester ([α]D= +105.2).
    • d2a) Alternatively (-)-(3aR,7aR)4-oxo-octahydro-indole-1-carboxylic acid tert-butyl ester can be obtained via the following procedure:
      To 11.76g (47.16 mmol) (3aRS,4SR,7aRS)-4-hydroxy-octahydro-indole-1-carboxylic acid tert-butyl ester in 50 ml TBME and 30g (34.8 mmol) vinyl acetate, 0.5g of immobilized lipase from Candida antarctica (Novozyme 435) is added and the mixture is stirred at room temperature for 24h. After filtration of the mixture, the solvent is removed and the obtained oily residue is purified by flash chromatography. The acetate (3aS,4R,7aS)-4-acetoxy-octahydro-indole-1-carboxylic acid tert-butyl ester is isolated in 47% yield with an optical purity of >99% (GC, [α]D 20=+54.6° c=1, MeOH).
      The recovered alcohol (3aR,4S,7aR)-4-hydroxy-octahydro-indole-1-carboxylic acid tert-butyl ester is obtained in 51% yield and >95% e.e.(GC, [α]D 20=-41.3° c=1, MeOH). Further purification by MPLC affords the alcohol with 99.5% purity and 99.5% e.e.
    • d2b) The alcohol (3aR,4S,7aR)-4-hydroxy-octahydro-indole-1-carboxylic acid tert-butyl ester is oxidized to the ketone as described in Example 1c) to yield (-)- (3aR,7aR)-4-oxo-octahydro-indole-1-carboxylic acid tert-butyl ester.
    • e) To a solution of 1-ethynyl-3-methyl-benzene (3.248 g; 28 mmol) in THF (168 ml) cooled to -20°C, a solution of butyllithium (17.5 ml; 28 mmol; 1.6M in hexane) is added. The reaction mixture is stirred at -20°C for 2 h then a solution of (-)-4-oxo-octahydro-indole-1-carboxylic acid tert-butyl ester (3.346 g; 14 mmol) in THF (70 ml) is added and the reaction mixture further stirred at 0-5°C. After 2 h the reaction mixture is diluted with ethylacetate (900 ml) and washed with sat. NaHCO3 (2X90 ml). The aqueous phase is extracted with ethylacetate (400 ml). The combined organic phases are dried over Na2SO4, filtered and evaporated in vacuo. The residue is purified by column chromatography on silica gel (300 g) and the fractions containing the desired compound are collected and evaporated in vacuo to yield (-)-(3aR,4S,7aR)-4-Hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid tert-butyl ester (4.27 g; yield = 85 %). 1H-NMR (400 MHz; DMSO-D6): δ 7.3-7.1 (m, 4H), 5.5 (d, J = 5 Hz, 1H), 3.85-3.65 (m, 1H), 3.35-3.25 (m, 1H), 3.25-3.1 (m, 1H), 2.6-2-45 (m, 1H), 2.28 (s, 3H), 1.9-1.4 (m, 7H), 1.36 (s, 9H), 1.13-0.98 (m, 1H).
    • f) (-)-(3aR,4S,7aR)-4-Hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid tert-butyl ester (4.27 g; 12 mmol) is dissolved in a solution of 1 M HCl in ethylacetate (240 ml) and stirred at room temperature for 6 h. After completion of of the hydrolysis (TLC) the solvent is evaporated in vacuo to yield (-)-(3aR,4S,7aR)-4-Hydroxy-4-m-tolylethynyl-octahydro-indole hydrochloride (3.39 g; yield = 93 %). m.p. = 181-183°C.
    • g) (-)-(3aR,4S,7aR)-4-Hydroxy-4-m-tolylethynyl-octahydro-indole hydrochloride (3.38 g; 11.6 mmol) is suspended in CH2Cl2 (174 ml), triethylamine (3.6 ml; 25.52 mmol) is added and the mixture is cooled to 5°C. Methylchloroformate (1.2 ml; 15.08 mmol) is added dropwise. After completion of the addition, the cooling bath is removed and the solution stirred for 2 h. The reaction mixture is diluted with CH2Cl2 (250 ml) and washed with brine (1 x 50 ml). The aqueous phase is extracted with CH2Cl2 (50 ml), the combined organic phases are dried over Na2SO4, filtered and the solvent evaporated in vacuo. The residue is column chromatographed on silica gel (240 g), eluent toluene/acetone 9:1 v/v. The fractions containing the desired compound are collected and evaporated in vacuo to yield 3.39 g of (-)-(3aR,4S,7aR)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester (yield = 90 %). M.p. = 110-112 °C. [α]D= -20.6 (c = 1, methanol).
  • Following the same procedure, the following compounds are obtained:
    • Example 1a: (-)-(3aR,4S,7aR)-4-Hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid ethyl ester
  • M.p. = 118-121 °C.
    • Example 1b: (-)-(3aR,4S,7aR)-Furan-2-yl-(4-hydroxy-4-m-tolylethynyl-octahydro-indol-1-yl)-methanone
  • M.p. = 195.5-196.5°C.
    • Example 1c: (±)-(3aRS,4SR,7aRS)-4-(3-Chlorophenylethynyl)-4-hydroxy-octahydro-indole-1-carboxylic acid ethyl ester
  • 1H NMR (400MHz; CDCl3): 1.27(t, 3H), 1.60-1.80(m, 4H), 1.88-2.11 (m, 5H), 2.27(m, 1H), 3.38(m, 1H), 3.54(m, 1H), 4.10(m, 2H), 7.22-7.31 (m, 3H), 7.40(m,1H).
    • Example 1d: (±)-(3aRS,4SR,7aRS)-4-(3-Fluoro-phenylethynyl)-4-hydroxy-octahydro-indole-1-carboxylic acid ethyl ester
  • HPLC-MS: 354 (M+Na).
    • Example 1e: (3aRS,4SR,7aRS)-4-Hydroxy-4-phenylethynyl-octahydro-indole-1-carboxylic acid(S)(tetrahydrofuran-3-yl)ester
  • ES-MS (+): 356 (M+1).
    • Example 1f: (3aRS,4SR,7aRS)-4-Hydroxy-4-phenylethynyl-octahydro-indole-1-carboxylic acid(R)(tetrahydrofuran-3-yl)ester
  • ES-MS (+): 356 (M+1).
    • Example 1g: (3aRS,4SR,7aRS)-4-Hydroxy-4-(3-chlorophenylethynyl)-octahydro-indol-1-carboxylic acid-(S)(tetrahydrofuran-3yl)ester
  • 1H NMR (400MHz; CHCl3): 7.39 (s, 1H), 7.25 (m, 3H), 5.27 (m, 1H),4.10-3.85 (m, 5H), 3.55 (m, 1H), 3.4 (m, 1H), 2.7 (m, 1H), 2.3 (s, 1H), 2.2-1.9 (m, 6H), 1.8-1.6 (m, 3H), 1.07 (m, 1H).
    • Example 1h: (±)-(3aRS,4SR,7aRS)-4-Hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid ethyl ester
  • ES-MS (+): 328.2 [M+1], m.p. = 123-124°C.
    • Example 1i: (±)-(3aRS,4SR,7aRS)-4-(4-Fluoro-phenylethynyl)-4-hydroxy-octahydro-indole-1-carboxylic acid ethyl ester
  • ES-MS (+): 332.2, m.p. = 115-116°C.
    • Example 1i: (±)-(3aRS,4SR,7aRS)-4-(3-chlorophenylethynyl)-4-hydroxy-1-methanesulfonyl-octahydro-indole
  • NMR (CDCI3): 7.41 (s,1H), 7.30 (m,3H), 3.93 (m,1H), 3.57 (m,1H), 3.35 (m,1H), 2.85 (s,3H), 2.69 (m,1H), 2.35 (bs,1H), 2.14 (m,1H), 2.0 (m,1H), 1.90, m,1H), 1.82-1.65 (m,4H), 1.35 (m,1H). HPLC: 1 peak, 99%
    • Example 2: (±)-(3aRS,7aRS)-4-Phenylethynyl-2,3,3a,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester and (±)-(RS)-4-phenylethynyl-2,3,5,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester
  • A solution of 4-hydroxy-4-phenylethynyl-octahydro-indole-1-carboxylic acid ethyl ester (1.0 g, 3.19 mmol), triethylamine (2.2 ml, 16 mmol) and phosphorous oxychloride 0.877 ml, 10 mmol) is heated to 40°C for 4 hours. The dark mixture is cooled to 0°C and treated with 1 M sodium hydroxide (5ml) and then acidified with a 10% aqueous citric acid solution. The mixture is extracted with dichloromethane, the organic extracts are washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue is chromatographed on silica with hexane and diethyl ether (4:1 v/v). The first product containing fractions afforded (±)-(RS)-4-phenylethynyl-2,3,5,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester (10 mg, 1 %) as a yellowish oil. 1H-NMR (400 MHz; CDCl3): 7.44 (m, 2H), 7.32 (m, 3H), 4.24 - 3.97 (m, 3H), 3.8 (m, 1H), 3.25 (m, 1H), 2.93 (m, 1H), 2.56 (m, 1H), 2.28 (m, 2H), 1.90 (m, 1H), 1.60 (m, 2H), 1.28 (t, J = 7 Hz, 3H), 1.14 (m,1H). ES-MS (+): 296.1. After collecting a mixture of the two products (475 mg, 50%), the third product containing fractions yielded (±)-(3RS,7aRS)-4-phenylethynyl-2,3,3a,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester (64 mg, 7%) as a yellowish oil. 1H-NMR (400 MHz; CDCl3): 7.43 (m, 2H), 7.31 (m, 3H), 6.27 (m, 1H), 4.15 (m, 2H), 4.01 - 3.83 (m, 1H), 3.46(m, 2H), 2.82 (m, 1H), 2.37-1.82 (m, 5H), 1.57 (m, 1H), 1.27 (t, J = 7 Hz, 3H). ES-MS (+): 296.2.
    • Following the same synthetic procedure the following examples can be made: Example 2a: (±)-(3RS,7aRS)-2,2,2-Trifluoro-1-(4-phenylethynyl-2,3,3a,6,7,7a-hexahydro-indol-1-yl)-ethanone
  • ES-MS (+): 320.3 (M+1), Rf = 0.62 (TLC silica gel, hexane/ethyl acetate 2:1).
    • Example 2b: (±)-(RS)-4-m-Tolylethynyl-2,3,5,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester
  • ES-MS (+): 310.2 (M+1), Rf = 0.55 (TLC silica gel, hexane/ethyl acetate 2:1).
    • Example 2c: (±)-(3RS,7aRS)-4-m-Tolylethynyl-2,3,3a,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester
  • ES-MS (+): 310.2 (M+1), Rf = 0.59 (TLC silica gel, hexane/ethyl acetate 2:1).
    • Example 2d: (±)-(3RS,7aRS)-4-(4-Chloro-phenylethynyl)-2,3,3a,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester
  • ES-MS (+): 330.2 (M+1), Rf = 0.56 (TLC silica gel, hexane/ethyl acetate 2:1).
    • Example 2e: (±)-(3RS,7aRS)-4-(2-Fluoro-phenylethynyl)-2,3,3a,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester
  • ES-MS (+): 314.2 (M+1), Rf = 0.42 (TLC silica gel, hexane/ethyl acetate 2:1).
    • Example 2f: (±)-(3RS,7aRS)-4-(3-Fluoro-phenylethynyl)-2,3,3a,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester
  • ES-MS (+): 314.2 (M+1).
    • Example 2g: (±)-(RS)-4-(3-Fluoro-phenylethynyl)-2,3,5,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester
  • ES-MS (+): 336.2 (M+Na).
    • Example 2h: (±)-(3RS,7aRS)-4-(3-Methoxy-phenylethynyl)-2,3,3a,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester
  • ES-MS (+): 348.2 (M+Na).
    • Example 2i: (±)-(RS)-4.-(3-Methoxy-phenylethynyl)-2,3,5,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester
  • ES-MS (+): 348.2 (M+Na).
    • Example 3: (±)-(3aRS,4RS,7aSR)-4-Hydroxy-4-phenylethynyl-octahydro-isoindole-2-carboxylic acid ethyl ester
    • a) A solution of 716 g acetic acid (±)-(3aRS,4RS,7aRS)-2-benzyl-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-yl ester [CAN 153255-27-7, see J.Chem.Soc. Perkin Trans I (1993), 1925-1929] in 3.5 l tetrahydrofuran is added dropwise to 300 g lithium aluminum hydride in 3.5 l tetrahydrofuran at 50°C. Thereafter the mixture is refluxed for 1H, then cooled to 0°C. 300ml water, followed by 300 ml 15% aqueous sodium hydroxide solution and again 600 ml water is added at max. 15°C. After filtration about 550 g slightly brown crystallizing oil, consisting of (±)-(3aRS,4SR,7aSR)-2-benzyl-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-ol is obtained. M.p. 69-71 C.
    • b) 1020 g (±)-(3aRS,4SR,7aSR)-2-benzyl-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-ol and 560 g oxalic acid dihydrate are dissolved in 18 l water, then hydrogenated using 200 g 10% palladium on charcoal catalyst at 100°C, 100 atm for 16h. After filtration of the catalyst the solution is concentrated to a volume of 6 l and 4.5 l dichloromethane are added. 810 g potassium hydroxide pellets are added portionwise, then ethyl chloro formate is added dropwise at a temperature not exceeding 30°C. The reaction mixture is extracted with dichloromethane, evaporated to yield 827 g (±)-(3aRS,4SR,7aSR)-4-hydroxy-octahydro-isoindole-2-carboxylic acid ethyl ester as slightly brown oil; purity by GC: 98.5%.
    • c) To 6.6 g oxalic chloride in 300 tetrahydrofuran at -60°C 7.4 g dimethylsulfoxide are added, then stirred for 15 min. 10 g (±)-(3aRS,4SR,7aSR)-4-hydroxy-octahydroisoindole-2-carboxylic acid ethyl ester in 50 ml tetrahydrofuran is added at -60°C, followed by 23 g triethylamine and allowed to warm at rt. The suspension is filtered, 400 ml ethyl acetate is added to the filtrate and the mixture washed with 3 times 400 ml water. Organic phases are dried with sodium sulfate and evaporated yielding 9.9 g (±)-(3aRS,7aSR)-4-oxo-octahydro-isoindole-2-carboxylic acid ethyl ester as crude brown oil. ES-MS(-): 210 (M-1), RP-HPLC: single peak.
    • d) 2.1 g (±)-(3aRS,7aSR)-4-oxo-octahydro-isoindole-2-carboxylic acid ethyl ester in 10 ml tetrahydrofuran is added at -10°C to 20 ml of 1 M lithium phenylacetylide in tetrahydrofuran within 10 min. After 16h at room temperature 100 ml saturated aqueous ammonium chloride solution is added, the mixture extracted with ethyl acetate, solvents dried over sodium sulfate and evaporated. The product is flash-chromatographed on silicagel with hexane/ethyl acetate (2:1). 2.2 g (±)-(3aRS,4RS,7aSR)-4-hydroxy-4-phenylethynyl-octahydro-isoindole-2-carboxylic acid ethyl ester are obtained as brown oil. ES-MS(+): 314 (M+1), RP-HPLC: single peak.
  • Following the same procedure the following compounds are obtained:
    • Example 3a: (±)-(3aRS,4RS,7aSR)-4-Hydroxy-4-m-tolylethynyl-octahydro-isoindole-2-carboxylic acid ethyl ester
  • ES-MS(+): 328 (M+1), RP-HPLC: single peak.
    • Example 3b: (±)-(3aRS,4RS,7aSR)-4-Hydroxy-4-p-tolylethynyl-octahydro-isoindole-2-carboxylic acid ethyl ester
  • HPLC-MS: single peak, 350 (M+Na).
    • Example 3c: (±)-(3aRS,4RS,7aSR)-4-(3-Cyano-phenylethynyl)-4-hydroxy-octahydroisoindole-2-carboxylic acid ethyl ester
  • HPLC-MS: single peak, 361 (M+Na).
    • Example 3d: (±)-(3aRS,4RS,7aSR)-4-Hydroxy-4-(3-methoxy-phenylethynyl)-octahydroisoindole-2-carboxylic acid ethyl ester
  • ES-MS(+): 344 (M+1), HPLC: single peak.
    • Example 3e: (±)-(3aRS,4RS,7aSR)-4-(3-Fluoro-phenylethynyl)-4-hydroxy-octahydroisoindole-2-carboxylic acid ethyl ester
  • ES-MS(+): 332 (M+1), HPLC: single peak.
    • Example 4: (±)-(3aRS,4RS,7aSR)-4-Hydroxy-4-phenylethynyl-octahydro-isoindole-2-carboxylic acid tert-butyl ester
    • a) Crude (±)-(3aRS,7aSR)-4-oxo-octahydro-isoindole-2-carboxylic acid tert-butyl ester is prepared in a 4-step procedure without purification: Starting from (3aSR,7aRS)-4-oxo-octahydro-isoindole-2-carboxylic acid ethyl ester: 1) Ketal formation with ethylene glycole in toluene/p-TsOH. 2) Removal of the ethyl carbamate using KOH in MeOH in sealed tube at 100°C. 3) Removal of ketal using 4N aqueous hydrochloric acid in acetone at room temperature. 4) Formation of the tert.-butyl carbamate using BOC-anhydride, K2CO3, in dichloromethane.
    • b) Reaction to (±)-(3aRS,4RS,7aSR)-4-hydroxy-4-phenylethynyl-octahydro-isoindole-2-carboxylic acid tert-butyl ester as described in Example 3d). ES-MS(+): 342 (M+1), RP-HPLC: single peak.
  • Following the same procedure, the following compound is obtained:
    • Example 4a: (±)-(3aRS,4RS,7aSR)-4-Hydroxy-4-m-tolylethynyl-octahydro-isoindole-2-carboxylic acid tert-butyl ester
  • ES-MS(+): 356 (M+1), RP-HPLC: single peak.
    • Example 5: (±)-(3aRS,4RS,7aSR)-4-Hydroxy-4-m-tolylethynyl-octahydro-isoindole-2-carboxylic acid methyl ester
    • a) 1 g of (±)-(3aRS,4RS,7aSR)-4-Hydroxy-4-m-tolylethynyl-octahydro-isoindole-2-carboxylic acid tert-butyl ester is treated with ca. 1 N HCl in ethyl acetate at room temperature for 18h, then washed with saturated sodium hydrogencarbonate solution. The organic phase is dried over Na2SO4 and evaporated. Purification by prep-HPLC. (±)-(3aRS,4RS,7aSR)-4-m-tolylethynyl-octahydro-isoindol-4-ol is obtained.
    • b) 60 mg of (±)-(3aRS,4RS,7aSR)-4-m-tolylethynyl-octahydro-isoindol-4-ol, 25 mg methyl chloroformate and 250 mg polymer-supported Hünig's base in 5 ml dichloromethane are stirred at room temperature for 18 h, then filtered and evaporated, followed by prep-HPLC purification to yield (±)-(3aRS,4RS,7aSR)-4-Hydroxy-4-m-tolylethynyl-octahydro-isoindole-2-carboxylic acid methyl ester. HPLC-MS: 336 (M+Na).
  • Following the same procedure, the following compounds are obtained:
    • Example 5a: (±)-(3aRS,4RS,7aSR)-Furan-2-yl-(4-hydroxy-4-m-tolylethynyl-octahydroisoindol-2-yl)-methanone
  • HPLC-MS: 372 (M+Na).
    • Example 5b: (±)-(3aRS,4RS,7aSR)-Cyclopropyl-(4-hydroxy-4-m-tolylethynyl-octahydroisoindol-2-yl)-methanone
  • HPLC-MS: 346 (M+Na).
    • Example 5c: (±)-(3aRS,4RS,7aSR)- (4-Hydroxy-4-m-tolylethynyl-octahydro-isoindol-2-yl)-pyridin-3-yl-methanone
  • HPLC-MS: 361 (M+1), 383 (M+Na).
    • Example 6: (±)-((1SR,3SR)-3-Hydroxy-3-m-tolylethynyl-cyclohexyl)-methyl-carbamic acid methyl ester and (±)-((1RS,3SR)-3-hydroxy-3-m-tolylethynyl-cyclohexyl)-methyl-carbamic acid methyl ester
    • a) To a solution of 3-methylamino-cyclohex-2-enone (1.35 g, 10.8 mmol; CAS 55998-74-8) and triethylamine (4.5 ml, 32.4 mmol) in dichloromethane (20 ml) is added methyl chloroformate (2.5 ml, 32.4 mmol) at 0°C during 15 minutes. After 45 minutes the reaction mixture is diluted with dichloromethane and washed three times with citric acid (10% w/v). The organic phase is concentrated in vacuo and the residue is treated with K2CO3 (3.0 g, 21.6 mmol) in water/methanol (1:1 v/v, 20 ml) for 15 minutes. The reaction mixture is concentrated in vacuo and the residue partitioned between water and dichloromethane and after concentration in vacuo the mixture is chromatographed on silica gel (100 g) with hexane / ethyl acetate (1:1 v/v) as eluent. The product methyl-(3-oxo-cyclohex-1-enyl)-carbamic acid methyl ester is obtained as a pale orange oil._NMR (400MHz; CDCl3): 5.68 (s, 1H), 3.79 (s, 3H), 3.20 (s,3H), 2.82 (t, J = 6.5 Hz, 2H), 2.39 (t, J = 6.5 Hz, 2H), 2.00 (quint., J = 6.5 Hz, 2H).
    • b) A solution of methyl-(3-oxo-cyclohex-1-enyl)-carbamic acid methyl ester (412 mg, 2.2 mmol) in methanol (20 ml) is hydrogenated with Pd/C (10 %, 80 mg, 1 bar). After filtration the crude product is chromatographed on silica gel (30 g) with hexane/ethyl acetate (1:1 v/v) as eluent. Methyl-(3-oxo-cyclohexyl)-carbamic acid methyl ester is obtained as a colorless oil._NMR (400MHz; CDCl3): 4.23 (br, 1H), 3.69 (s, 3H), 2.83 (br,s, 3H), 2.57 - 2.34 (m, 3H), 2.21 (td, J = 14 Hz, J = 6 Hz, 1H), 2.05 (m, 1H), 1.91 (m, 1H), 1.80 (qd, J = 12.5 Hz, J = 3.5 Hz, 1H), 1.6 (m, 1H).
    • c) The reaction of methyl-(3-oxo-cyclohexyl)-carbamic acid methyl ester with lithium m-tolylacetylide is performed as in example 1. After chromatography on silicagel with hexane/ethyl acetate (gradient 4:1 to 1:1 v/v) as eluent the title compound (±)-((1SR,3SR)-3-hydroxy-3-m-tolylethynyl-cyclohexyl)-methyl-carbamic acid methyl ester (yield 24%) is first eluted (Rf = 0.62 (TLC silica gel, hexane/ethyl acetate 1:1), HPLC-MS: 324.2 (M+Na)+) followed by (±)-((1RS,3SR)-3-hydroxy-3-m-tolylethynyl-cyclohexyl)-methyl-carbamic acid methyl ester (yield 50%, Rf = 0.49 (TLC silica gel, hexane/ethyl acetate 1:1), HPLC-MS: 324.2 (M+Na)+).
  • Following the same procedure the following compounds are obtained:
    • Example 6a: (±)-(1RS,3SR)-((3-Hydroxy-3-m-tolylethynyl-cyclohexyl)-(4-methoxy-benzyl)-carbamic acid ethyl ester.
  • HPLC-MS: 444.2 (M+Na)+.
    • Example 6b: (±)-(1RS,3RS)-((3-Hydroxy-3-m-tolylethynyl-cyclohexyl)-(4-methoxy-benzyl)-carbamic acid ethyl ester.
  • HPLC-MS: 444.2 (M+Na)+.
    • Example 6c: (±)-[(1RS,3SR)-3-Hydroxy-3-(3-methoxy-phenylethynyl)-5,5-dimethylcyclohexyl]-methyl-carbamic acid methyl ester.
  • HPLC-MS: 368.2 (M+Na)+.
    • Example 6d: (±)-(1RS,3SR)-(3-Hydroxy-5,5-dimethyl-3-m-tolylethynyl-cyclohexyl)-methyl-carbamic acid methyl ester.
  • HPLC-MS: 352.2 (M+Na)+.
    • Example 6e: (±)-[(1RS,3SR)-3-(3-Fluoro-phenylethynyl)-3-hydroxy-5,5-dimethyl-cyclohexyl]-methyl-carbamic acid methyl ester
  • HPLC-MS: 356.2 (M+Na)+.
    • Example 6f: (±)-[(1RS,3RS)-3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-methyl-carbamic acid methyl ester.
  • HPLC-MS: 328.2 (M+Na)+.
    • Example 6g: (±)-[(1RS,3SR)-3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-methyl-carbamic acid methyl ester.
  • HPLC-MS: 328.2 (M+Na)+.
    • Example 6h: (±)-[(1RS,3RS)-3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexy]-methyl-carbamic acid methyl ester.
  • HPLC-MS: 340.2 (M+Na)+.
    • Example 6i: (±)-[(1RS,3SR)-3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-methyl-carbamic acid methyl ester.
  • HPLC-MS: 340.2 (M+Na)+.
    • Example 6i: (±)-[(1RS,3RS)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-methyl-carbamic acid methyl ester.
  • Rf = 0.31 (TLC silica gel, hexane/ethyl acetate 1:1).
    • Example 6k: (±)-[(1 RS,3SR)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-methyl-carbamic acid methyl ester.
  • Rf = 0.22 (TLC silica gel, hexane/ethyl acetate 1:1).
    • Example 6l: (±)-(1RS,3RS)-N-(3-hydroxy-3-m-tolyethynyl-cyclohexyl)-acetamide
  • HPLC-MS: 294.2 (M+Na).
    • Example 6m: (±)-(1RS,3SR)-N-(3-hydroxy-3-m-tolytethynyl-cyclohexyl)-acetamide
  • M.p. 152-155°C.
    • Example 6n: (±)-(1 RS,3RS)-(3-Hydroxy-3-m-tolylethynyl-cyclohexyl)-carbamic acid ethyl ester
  • HPLC-MS: 324.2 (M+Na).
    • Example 6o: (±)-(1RS,3SR)-(3-Hydroxy-3-m-tolylethynyl-cyclohexyl)-carbamic acid ethyl ester
  • M.p. 106-107°C.
    • Example 6p: (±)-(1RS,3RS)-[3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbamic acid ethyl ester
  • HPLC-MS: 328.2 (M+Na).
    • Example 6g: (±)-(1RS,3SR)-[3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbamic acid ethyl ester
  • M.p. 121-123°C.
    • Example 6r: (±)-(1RS,3RS)-[3-(3-Methoxy-phenylethynyl)-3-hydroxy-cyclohexyl]-carbamic acid ethyl ester
  • HPLC-MS: 340.2 (M+Na).
    • Example 6s: (±)-(1RS,3RS)-N-[3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-acetamideHPLC-MS: 340.2 (M+Na). Example 6t: (±)-(1RS,3SR)-N-[3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-acetamide
  • HPLC-MS: 276.2 (M+1), 298.2 (M+Na).
    • Example 6u: (±)-(1RS,3SR)-[3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-carbamic acid ethyl ester
  • HPLC-MS: 340.2 (M+Na).
    • Example 6v: (±)-(1RS,3RS)-N-[3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-acetamide
  • HPLC-MS: 288.2 (M+1), 310.2 (M+Na).
    • Example 6w: (±)-(1RS,3SR)-N-[3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-acetamide HPLC-MS: 288.2 (M+1), 310.2 (M+Na). Example 6x: (±)-(1RS,3RS)-[3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-carbamic acid tert-butyl ester
  • HPLC-MS: 368.2 (M+Na).
    • Example 6y: (±)-(1 RS,3SR)-[3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-carbamic acid tert-butyl ester
  • HPLC-MS: 368.2 (M+Na).
    • Example 6z: (±)-(1RS,3RS)-(3-Hydroxy-3-m-tolylethynyl-cyclohexyl)-carbamic acid tert-butyl ester
  • HPLC-MS: 352.2 (M+Na).
    • Example 6aa: (±)-(1RS,3SR)-(3-Hydroxy-3-m-tolylethynyl-cyclohexyl)-carbamic acid tert-butyl ester
  • HPLC-MS: 352.1 (M+Na).
    • Example 6ab: (±)-(1RS,3RS)-(3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbamic acid tert-butyl ester
  • HPLC-MS: 356.2 (M+Na).
    • Example 6ac: (±)-(1RS,3SR)-(3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbamic acid tert-butyl ester
  • HPLC-MS: 356.2 (M+Na).
    • Example 6ad: (±)-(1RS,3RS)-[3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbamic acid methyl ester
  • HPLC-MS: 314.2 (M+Na).
    • Example 6ae: (±)-(1RS,3SR)-[3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbamic acid methyl ester
  • HPLC-MS: 314.2 (M+Na).
    • Example 7: (±)-(3-Phenylethynyl-cyclohex-2-enyl)-carbamic acid ethyl ester and (±)-3-phenylethynyl-cyclohex-3-enyl)-carbamic acid ethyl ester
  • 100 mg (0.35 mmol) (3-hydroxy-3-phenylethynyl-cyclohexyl)-carbamic acid ethyl ester (diasteromeric mixture 2) in 15 mL toluene are treated with 10 mg p-toluene sulfonic acid and stirred 6 hours at 120°. After cooling and addition of 50 ml ethyl acetate, the product is washed with water containing a small amount of sodium bicarbonate, and saline. The organic phase is dried with sodium sulfate, concentrated and column chromatographed using a 3:1 mixture of petroleum ether and ethyl acetate. The first product to come out of the column is (3-phenylethynyl-cyclohex-2-enyl)-carbamic acid ethyl ester (yield, 23%), followed by (3-phenylethynyl-cyclohex-3-enyl)-carbamic acid ethyl ester (yield: 48%)
    Racemate 1: 1H-NMR (400 MHz): delta = 7.41 (m, 2H); 7.30 (m, 3H); 6.04 (s, 1H); 4.63 (broad s, 1H); 4.35 (broad s, 1H); 4.10 (q, 2H); 2.20 (s, 2H); 1.90 (m, 1H); 1.70, (m, 2H); 1.50 (m, 1H); 1.23 (t, 3H).
    Racemate 2: 1H-NMR (400 MHz): delta = 7.40 (m, 2H); 7.30 (m, 3H); 6.19 (s, 1H); 4.68 (broad s, 1H); 4.10 (q, 2H); 3.92 (broad s, 1H); 2.61 (d, 1H); 2.28 (broad s, 2H); 2.12, 1.85, 1.59 (3m, 3H); 1.23 (t, 3H).
    • Example 8: (±)-Methyl-(3-phenylethynyl-cyclohex-3-enyl)-carbamic acid ethyl ester
  • 22 mg (0.082 mmol) (3-phenylethynyl-cyclohex-3-enyl)-carbamic acid ethyl ester are dissolved in 2ml DMF and 1 mL THF. 8 mg (0.165 mmol) of a 60% dispersion of NaH in oil is added and the mixture stirred under argon for 90 minutes at room temperature. The reaction mixture is cooled to 0°, and 16 microliters Mel in 0.5 ml THF are added dropwise. After stirring one hour at room tenmperature, the reaction mixture is cooled to 0° again, ice is added and the crude product extracted with ethyl acetate, washed with water and saline, dried with sodium sulfate and column chromatographed using a 4:1 mixture of petroleum ether and ethyl acetate. Yield: 43% .
    1H-NMR (400 MHz): delta = 7.40 (m, 2H); 7.30 (m, 3H); 6.18 (s, 1H); 4.22 (broad m, 1H); 4.15 (q, 2H); 2.8 (broad s, 3H); 2.35 (broad s, 4H); 1.80-1.60 (m, 1H); 1.15 (t, 3H).
    • Example 9: (±)-(4aRS,5RS,8aSR)-5-Hydroxy-5-phenylethynyl-octahydro-quinoline-1-carboxylic acid ethyl ester
    • a) To the mixture of (±)-(4aRS,8aSR)-octahydro-quinolin-5-one oxalate (1.50g, 6.17mmol), toluene (5ml) and water (5ml) is added solid potassium carbonate. After stirring for a few minutes ethyl chloroformate (0.71 ml, 7.4mmol) is added and the reaction mixture is then stirred at room temperature for 3 hours. The organic phase is separated and the aqueous phase extracted with dichloromethane (3x10ml). The combined organic phases are dried over magnesium sulphate and concentrated in vacuo to yield 1.22g (88%) of (±)-(4aRS,8aSR)-5-Oxo-octahydro-quinoline-1-carboxylic acid ethyl ester. 1H NMR (400MHz; CDCl3): 1.28 (t, 3H), 1.40 1.70 (m, 3H), 1.72-1.90 (m, 1H), 2.0-2.20 (m, 3H), 2.30-2.48 (m, 3H), 2.55 (td, 1H), 3.32 (td, 1H), 3.50 (m, 2H), 4.12 (q, 2H).
    • b) To a solution of (±)-(4aRS,8aSR)-5-oxo-octahydro-quinoline-1-carboxylic acid ethyl ester (0.372g, 1.65mmol) in THF (15ml) is added a solution of lithium phenylacetylide in THF (3.30ml, 3.30mmol; 1.0M solution in THF) at -50C. The reaction mixture is then stirred for 1.5 hours at -50C and then allowed to warm to room temperature. The reaction mixture is diluted with diethyl ether (100ml), washed with saturated sodium bicarbonate solution (2×10ml), water (10ml), dried over magnesium sulfate and then concentrated in vacuo. Purification of the crude product (0.860g) using silica gel chromatography (ethylacetate/hexane 1:3 v/v ) give (±)-(4aRS,5RS,8aSR)-5-hydroxy-5-phenylethynyl-octahydro-quinoline-1-carboxylic acid ethyl ester.(0.144g, 26.7%).
  • Following the same procedure the following compounds are obtained:
    • Example 9a: (±)-[(4aRS,5SR,8aSR)-5-(3-Chloro-phenylethynyl)-5-hydroxy-octahydro-quinolin-1-yl]-furan-2-yl-methanone
  • NMR (DMSO-D6, 500MHz): 7.84 (s,1H), 7.45 (m,4H), 6.95 (d,1H), 6.63 (d,1H), 5.51 (s,1H), 4.03 (m,1H), 3.94 (m,1H), 3.32 (m,1H), 2.06 (m,1H), 2.04 (m,1H), 1.96 (m,1H), 1.94 (m,1H), 1.85 (m,1H), 1.74 (m.2H), 1.71 (m,1H), 1.60 (m,1H), 1.50 (m,1H), 1.41 (m,1H).
    • Example 9b: (±)-[(4aRS,5RS,8aSR)-5-(3-Chloro-phenylethynyl)-5-hydroxy-octahydro-quinolin-1-yl]-furan-2-yl-methanone
  • NMR (DMSO-D6, 500MHz): 7.83 (s,1H), 7.43 (m,4H), 6.95 (d,1H), 6.62 (m,1H), 5.77 (s,1H), 3.99 (m,1H), 3.90 (m,1H), 3.31 (m,1H), 2.12 (m,1H), 2.06 (m,1H), 1.97 (m,1H), 1.88 (m,1H), 1.83 (m,1H), 1.77 (m,1H), 1.66 (m,1H), 1.59 (m,2H), 1.46 (m,1H), 1.22 (m,1H).
    • Example 9c: (±)-(4aRS,5RS,8aSR)-5-(3-Chloro-phenylethynyl)-5-hydroxy-octahydroquinoline-1-carboxylic acid tert-butyl ester
  • NMR (CDCl3): 7.42 (d,J=1.1Hz, 1H), 7.32 (m,3H), 3.55 (m,1H), 3.48 (m,1H), 3.10 (m,1H), 2.08 (m,3H), 1.90 (m,1H), 1.8-1.6 (m,7H), 1.46 (s,9H), 1.38 (m,1H).
    • Example 9d: (±)-[(4aRS,5SR,8aSR)-5-(3-Chloro-phenylethynyl)-5-hydroxy-octahydro-quinolin-1-yl]-morpholin-4-yl-methanone
  • LC-MS, M+1=403.1
    • Example 9e: (±)-[(4aRS,5SR,8aSR)-5-(3-chloro-phenylethynyl)-5-hydroxy-octahydro-quinolin-1-yl]-(4-methyl-piperazin-1-yl)-methanone
  • LC-MS, M+1= 416.2
    • Example 10: (±)-(4aRS,5RS,8aSR)-5-(3-chloro-phenylethynyl)-5-hydroxy-octahydroquinoline-1-carboxylic acid ethyl ester and (±)-(4aRS,5SR,8aSR)- 5-(3-chloro-phenylethynyl)-5-hydroxy-octahydro-quinoline-1-carboxylic acid ethyl ester
    • a) To a solution of trimethylsilylacetylene (1.54ml, 10.8mmol) in THF (10ml), is added a solution of n-butyllithium in hexane (6.75ml, 10.8mmol; 1.6M in hexane) at 0°C. The reaction mixture is stirred at 0°C for 45 minutes and then at room temperature for 20 hours. The reaction mixture is diluted with diethyl ether (100ml), washed with saturated sodium bicarbonate solution (2×10ml), dried over magnesium sulfate and concentrated in vacuo. Purification of the crude product (2.0 g) using silica gel chromatography (ethylacetate/hexane gradient 0-40% v/v) give (±)-(4aRS,5RS,8aSR)-5-hydroxy-5-trimethylsilanylethynyl-octahydro-quinoline-1-carboxylic acid ethyl ester. (1.48, 84%); 1H NMR (400MHz; CDCl3): 1H NMR 0.1 (s-overlap, 9H), 1.05 (t, 3H), 1.10-1.30 (m, 2H ),1.30-1.60 (m, 6H), 1.60-1.95 (m, 4H), 2.80-3.0 (m,1H), 3.25-3.50 (m, 1H), 3.50-3.65 (m, 1H), 3.95(m, 2H). Further chromatographic fractions all contain variable mixtures of (±)-(4aRS,5RS,8aSR)-5-hydroxy-5-trimethylsilanylethynyl-octahydro-quinoline-1-carboxylic acid ethyl ester and (±)-(4aRS,5SR,8aSR)-5-hydroxy-5-trimethylsilanylethynyl-octahydroquinoline-1-carboxylic acid ethyl ester.
    • b) A mixture (approximately 5 :1) of (±)-(4aRS,5RS,8aSR)-5-hydroxy-5-trimethylsilanylethynyl-octahydro-quinoline-1-carboxylic acid ethyl ester and (±)-(4aRS,5SR,8aSR)-5-hydroxy-5-trimethylsilanylethynyl-octahydro-quinoline-1-carboxylic acid ethyl ester (0.272g, 0.84mmol), 1-bromo-3-chloro-benzene (0.161g, 0.84 mmol), copper(I)iodide (0.016g, 0.093mmol), triphenylphosphine (0.02g, 0.074mmol), potassium carbonate (0.127g, 0.92mmol), palladium on carbon (10%) (10 mg) in dimethoxyethane (2ml) and water (1ml) are combined together and heated at 80°C for 24hours under argon atmosphere. The reaction mixture is cooled to room temperature, filtered through celite, washed with diethyl ether and concentrated in in vacuo to yield a crude oil. The crude oil (0.181 g) is purified using silica gel chromatography (ethylacetate / hexane gradient 0-30%) and fractions containing the desired compounds are collected and evaporated in vacuo to yield the first product (±)-(4aRS,5RS,8aSR)-5-(3-chloro-phenylethynyl)-5-hydroxy-octahydro-quinoline-1-carboxylic acid ethyl ester. (140mg, 46%). 1H NMR (400MHz; CDCI3): 1.28 (t, 3H), 1.2 8-1.50 (m, 2H), 1.50 -2.00 (m, 7H), 2.0-2.20 (m, 3H), 3.08 (m,1H), 3.55 (tm, 1H), 3.80 (m, 1H), 4.15 (q, 2H),7.24-7.40(m, 4H) and the second product (±)-(4aRS,5SR,8aSR)-5-(3-chloro-phenylethynyl)-5-hydroxy-octahydro-quinoline-1-carboxylic acid ethyl ester (30mg, 10%). 1H NMR (400MHz; CDCI3): 1.29 (t, 3H), 1.41-1.58(m, 2H), 1.58 -2.00(m, 8H), 2.08-2.18 (m, 2H), 3.16 (m,1H), 3.61 (m, 1H), 3.70 (m, 1H), 4.10 (m, 2H),7.16 -7.30(m, 4H).
  • Following the same procedure the following compounds are obtained:
    • Example 10a: (±)-(4aRS,5SR,8aSR)-5-Hydroxy-5-m-tolylethynyl-octahydro-guinoline-1-carboxylic acid ethyl ester
  • 1H NMR (400MHz; CDCl3): 1.25 (t, 3H), 1.39 -1.56 (m, 2H), 1.56-1.98 (m, 8H), 1.98-2.23 (m, 2H), 2.35 (s, 3H), 3.15 (m, 1H), 3.55-3.79 (m, 2H), 4.04-4.20 (m, 2H),7.10 (m, 1H)7.15-7.25 (m, 3H)
    • Example 10b: (±)-(4aRS,5RS,8aSR)-5-Hydroxy-5-m-tolylethynyl-octahydro-quinoline-1-carboxylic acid ethyl ester
  • 1H NMR (400MHz; CDCl3): 1.25 (t, 3H), 1.30-1.50 (m, 2H), 1.56-2.20 (m, 8H), 2.20-2.44 (m, 3H), 2.85-3.19(m,1H), 3.54-3.63 (m, 1H), 3.69-3.84 (m, 1H), 4.07-4.19 (m, 2H),7.05 - 7.27 (m, 4H).
    • Example 11: (±)-Ethyl-((1SR,3SR)-3-hydroxy-3-m-tolylethynyl-cyclopentyl)-carbamic acid methyl ester and (±)-ethyl-((1SR,3RS-3-hydroxy-3-m-tolylethynyl-cyclopentyl)-carbamic acid methyl ester
    • a) To a solution of 3-methoxy-cyclopent-2-enone (800 mg, 7.13 mmol) in 30 ml of an ethylamine solution in THF, (2.0 M, 60 mmol) acetic acid (200 µl) is added and the mixture stirred at 70 °C for 2 h. The reaction mixture is concentrated in vacuo and the residue is filtered through silica gel with acetone. The resulting solid is crystallized from dichloromethane / ether to yield 3-ethylamino-cyclopent-2-enone as white crystals, m.p. 136-136.5°C.
    • b) To a solution of 3-ethylamino-cyclopent-2-enone (500 mg, 4mmol) in 4ml THF and 1 ml DMF, sodium hydride (12 mmol) is added. After stirring the reaction mixture for 20 minutes at room temperature, methyl chloroformate (615 µl, 8 mmol) is added. After stirring for 15 minutes, the reaction mixture is quenched with saturated aqueous ammonium chloride solution and concentrated in vacuo.The residue is partitioned between brine and dichloromethane. The organic extracts are chromatographed on silica gel (30 g) with dichloromethane/methanol (95:5 v/v) as eluent to afford ethyl-(3-oxo-cyclopent-1-enyl)-carbamic acid methyl ester which is crystallized from dichloromethane /ether, m.p. 68-68.5°C.
    • c) Ethyl-(3-oxo-cyclopent-1-enyl)-carbamic acid methyl ester (400mg, 2.18 mmol) is hydrogenated in methanol with Pd/C (10%, 80mg) to yield (±)-ethyl-((R,S)-3-oxo-cyclopentyl)-carbamic acid methyl ester as a yellowish oil.
    • d) The reaction of (±)-ethyl-((R,S)-3-oxo-cyclopentyl)-carbamic acid methyl ester with lithium m-tolylacetylide is performed as in example 1. After chromatography on silicagel with hexane/acetone (5:1 v/v) as eluent, the title compound (±)-ethyl-((1 SR,3RS)-3-hydroxy-3-m-tolylethynyl-cyclopentyl)-carbamic acid methyl ester is first eluted [Rf = 0.48 (TLC silica gel, hexane/ethyl acetate 1:1), HPLC-MS: 324.2 (M+Na)+] followed by (±)-ethyl-((1SR,3SR)-3-hydroxy-3-m-tolylethynyl-cyclopentyl)-carbamic acid methyl ester [Rf = 0.39 (TLC silica gel, hexane/ethyl acetate 1:1), HPLC-MS: 324.2 (M+Na)+], both as pale yellow oils.

Claims (10)

  1. A compound of formula (I)
    Figure imgb0004
     wherein
    m is 0 or 1;
    n is 0 or 1;
    A is hydroxyl and X is hydrogen and Y is hydrogen, or
    A forms a single bond with X or with Y;
    R0 is hydrogen, (C1-4)alkyl, (C1-4)alkoxy, trifluoromethyl, halogen, cyano, nitro, -COOR1 wherein R1 is (C1-4)alkyl or -COR2 wherein R2 is hydrogen or (C1-4)alkyl, and
    R is -COR3, -COOR3, -CONR4R5 or -SO2R6, wherein R3 is (C1-4)alkyl, (C3-7)cycloalkyl or optionally substituted phenyl. 2-pyridyl or 2-thienyl, R4 and R6, independently, are hydrogen or (C1-4)alkyl and R6 is (C1-4)alkyl, (C3-7)cycloalkyl or optionally substituted phenyl,
    R' is hydrogen or (C1-4)alkyl and R" is hydrogen or (C1-4)alkyl, or
    R' and R" together form a group -CH2-(CH2)m- wherein m is 0.1 or 2, in which case one of n and m is different from 0,
    with the proviso that R0 is different from hydrogen, trifluoromethyl and methoxy when m is 1, n is 0, A is hydroxy, X and Y are both hydrogen, R is COOEt and R' and R" together form a group -(CH2)2-,
    in free base or pharmaceutically acceptable acid addition salt form, for use as a pharmaceutical.
  2. A compound selected from the following list, in free base or acid addition salt form:
    1: (-)-(3aR,4S,7aR)-4-Hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester
    1a: (-)-(3aR,4S,7aR)-4-Hydroxy-4-3-tolylethynyl-octahydro-indole-1-carboxylic acid ethyl ester
    1b: (-)-(3aR,4S,7aR)-Furan-2-yl-(4-hydroxy-4-m-tolylethynyl-actahydro-indol-1-yl)-methanone
    1c: (±)-(3aRS,4SR,7aRS)-4-(3-Chlorophenylethynyl)-4-hydroxy-octahydro-indole-1-carboxylic acid ethyl ester
    1d: (±)-(3aRS,4SR,7aRS)-4-(3-Fluoro-phenylethynyl)-4-hydroxy-octahydro-indole-1-carboxylic acid ethyl ester
    1e: (3aRS,4SR,7aRS)-4-Hydroxy-4-phenylethynyl-octahydro-indole-1-carboxylic acid(S)(tatrahydrofuran-3-yl)ester
    1f: (3aRS,4SR,7aRS)4-Hydroxy-4-phenylethynyl-octahydro-indole-1-carboxylic acid(R)(tetrahydrofuran-3-yl)ester
    1g: (3aRS,4SR,7aRS)-4-Hydroxy-4-(3-chlorophenylethynyl)-octahydro-indol-1-carboxylic acid-(S)(tetrahydrofuran-3yl)ester
    1h: (±)-(3aRS,4SR, 7aRS)4-Hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid ethyl ester
    1i: (±)-(3aRS,4SR,7aRS)-4-(4-Fluoro-phenylethynyl)-4-hydroxy-octahydro-indole-1-carboxylic acid ethyl ester
    1j: (±)-(3aRS,4SR,7aRS)-4-(3-chlorophenylethynyl)-4-hydroxy-1-methansulfonyl-octahydro-indole
    2: (±)-(3aRS,7aRS)-4-Phenylethynyl-2,3,3a,6,7,7a-hetahydro-indole-1-carboxylic acid ethyl ester and (±)-(RS)-4-phenylethynyl-2,3,5,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester
    2a: (±)-(3RS,7aRS)-2,2,2-Trifluoro-1-(4-phenylethynyl-2,3,3a,6,7,7a-hexahydro-indol-1-yl)-ethanone
    2b: (±)-(RS)-4-m-Tolylethynyl-2,3,5,6,7,7a-hexahydro-indol-1-carboxylic acid ethyl ester
    2c: (±)-(3RS,7aRS)4-m-Tolylethynyl-2,3,3a,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester
    2d: (±)-(3RS,7aRS)-4-(4-Chloro-phenylethynyl)-2,3,3a,6,7,'7a-hexahydro-indole-1-carboxylic acid ethyl ester
    2e: (±)-(3RS,7aRS)-4-(2-Fluoro-phenylethynyl)-2,3,3a,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester
    2f: (±)-(3RS,7aRS)-4-(3-Fluoro-phenylethynyl)-2,3,3a,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester
    2g: (±)-(RSY4-(3-Fluoro-phenylethynyl)-2,3,5,6.7,7a-hexahydro-indole-1-carboxylic acid ethyl ester
    2h: (±)-(3RS,7aRS)- 4-(3-Methoxy phenylethynyl)-2,3,3a,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester
    2i: (±)-(RS)-4-(3-Methoxy-phenylethynyl)-2,3,5,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester
    3: (±)-(3aRS,4RS,7aSR)-4-Hydroxy-4-phenylethynyl-octahydro-isoindole-2-carboxylic acid ethyl ester
    3a: (±)-(3aRS,4RS,7aSR)-4-Hydroxy-4-m-tolylethynyl-octahydro-isoindole-2-carboxylic acid ethyl ester
    3b: (±)-(3aRS,4RS,7aSR)-4-Hydroxy-4-p-tolylethynyl-octahydro-isoindole-2-carboxylic acid ethyl ester
    3e: (±)-(3aRS,4RS,7aSR)-4-(3-Cyano-phenylethynyl)-4-hydroxy-octahydro-isoindole-2-carboxylic acid ethyl ester
    3d: (±)-(3aRS,4RS,7aSR)-4-Hydroxy-4-(3-methoxy-phenylethynyl)-octahydro-isoindole-2-carboxylic acid ethyl ester
    3e: (±)-(3aRS, 4RS, 7aSR)-4-(3-Fluoro-phenylethynyl)-4-hydroxy-octahydro-isoindole-2-carboxylic acid ethyl ester
    4: (±)-(3aRS,4RS,7aSR)-4-Hydroxy-4-phenylethynyl-octahydro-isoindole-2-carboxylic acid tert-butyl ester
    4a: (±)-(3aRS,4RS,7aSR)-4-Hydroxy-4-m-tolylethynyl-octahydro-isoindole-2-carboxylic acid tert-butyl ester
    5: (±)-(3aRS,4RS,7aSR)-4-Hydroxy-4-m-tolylethynyl-octahydro-isoindole-2-carboxylic acid methyl ester
    5a: (±)-(3aRS,4R5,7aSR)-Furan-2-yl-(4-hydroxy-4-m-tolylethynyl-octahydro-isoindol-2-yl)-methanone
    5b: (±)-(3aRS, 4RS, 7aSR)-Cyclopropyl-(4-hydroxy-4-m-tolylethynyl-octahydro-isoindol-2-yl)-methmone
    5c: (±)-(3aRS,4RS,7aSR)- (4-Hydroxy-4-m-tolylethynyl-octahydro-isoindol-2-yl)-Pyridin-3-yl-methanone
    6: (±)-((1SR,3SR)-3-Hydroxy-3-m-tolylethynyl-cyclohekyl)-methyl-carbamic acid methyl ester and (±)-((1RS,3SR)-3-hydroxy-3-m-tolylethynyl-cyelohexyl)-methyl-carbamic acid methyl ester
    6a: (±)-(1RS,3SR)-((3-Hydroxy-3-m-tolylethynyl-cyctohexyl)-(4-methoxy-benzyl)-carbamic acid ethyl ester.
    6b: (±)-(1RS,3RS)-(3-Hydroxy-3-m-tolylethynyl-cyclohexyl)-(4-methoxy-benzyl)-carbamic acid ethyl ester.
    6c: (±)-[(1RS,3SR)-3-Hydroxy-3-(3-methoxy-phenylethynyl)-5,5-dimethyl-cyclohexyl]-methyl-carbamic acid methyl ester.
    6d: (±)-(1RS,3SR)-(3-Hydroxy-5,5-dimethyl-3-m-tolylethynyl-cyclohexyl)-methyl-carbamic acid methyl ester.
    6e: (±)-[(1RS,3SR)-3-(3-Fluoro-phenylethynyl)-3-hydroxy-5,5-dimethyl-cyclohexyl]-methyl-carbamic acid methyl ester
    6f: (±)-[(1RS,3RS)-3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-methyl-carbamic acid methyl ester.
    6g: (±)-[(1RS,3SR)-3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-methyl-carbamic acid methyl ester.
    6h: (±)-[(1RS,3RS)-3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-methyl-carbamic acid methyl ester.
    6i: (±)-[(1RS,3SR)-3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-methyl-carbamic acid methyl ester.
    6j: (±)-[(1RS,3RS)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-methyl-carbamic acid methyl ester.
    6k: (±)-[(1RS,3SR)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-methyl-carbamic acid methyl ester.
    6l: (±)-(1RS,3RS)-N-(3-hydroxy-3-m-tolylethynyl-cyclohexyl)-acetamide
    6m: (±)-(1RS,3SR)-N-(3-hydroxy-3-m-tolylethynyl-cyclohexyl)-acetamide
    6n: (±)-(1RS,3RS)-(3-Hydroxy-3-m-tolylethynyl-cyclohexyl)-carbamic acid ethyl ester
    6o: (±)-(1RS,3SR)-(3-Hydroxy-3-m-tolylethynyl-cyclohexyl)-carbamic acid ethyl ester
    6p: (±)-(1RS,3RS)-[3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbamic acid ethyl ester
    6q: (±)-(1RS,3SR)-[3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl-carbamic acid ethyl ester
    6r: (±)-(1RS,3RS)-[3-(3-Methoxy-phenylethynyl)-3-hydroxyl-cyclohexyl]-carbonic acid ethyl ester
    6s: (±)-(1RS,3RS)-N-[3-(3-Fluora-phenylethynyl)-3-hydroxy-cyclohexyl]-acetamide
    6t: (±)-(1RS,3SR)-N-[3-3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-acetamide
    6u: (±)-(1RS,3SR)-[3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-carbamic acid ethyl ester
    6v: (±)-(1RS,3RS)-N-[3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-acetamide
    6w: (±)-(1RS,3SR)-N-[3-Hydroxy-3-(3 methoxy-phenylethynyl)-cyclohcexyl]-acetamide
    6x: (±)-(1RS,3RS)-[3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-carbamic acid tert-butyl ester
    6y: (±)-(1RS,3SR)-[3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-carbamic acid tert-butyl ester
    6z: (±)-(1RS,3RS)-(3-Hydroxy-3-m-tolylethynyl-cyclohexyl)-carbamic acid tert-butyl ester
    6aa: (±)-(1RS,3SR)-(3-Hydroxy-3-m-tolylethynyl-cyclohexyl)-carbamic acid tert-butyl ester
    6ab: (±)-(1RS,3RS)-[3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbamic acid tert-butyl ester
    6ac: (±)-(1RS,3SR)-[3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbamic acid tert-butyl ester
    6ad: (±)-(1RS,3RS)-[3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbamic acid methyl ester
    6ae: (±)-(1RS,3SR)-[3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbamic acid methyl ester
    7: (±)-(3-Phenylethynyl-cyclohex-2-enyl)-carbamic acid ethyl ester and (±)-3-phenylethynyl-cyclohex-3-enyl)-carbamic acid ethyl ester
    8: (±)-Methyl-(3-phenylethynyl-cyclohex-3-enyl)-carbamic acid ethyl ester
    9: (±)-(4aRS,5RS,8aSR)-5-Hydroxy-5-phenylethynyl-octahydro-quinoline-1-carboxylic acid ethyl ester
    9a: (±)-[(4aRS,5SR,8aSR)-5-(3-Chloro-phenylethynyl)-5-hydroxy-octahydro-quinolin-1-yl]-furan-2-yl-methanone
    9b: (±)-[(4aRS,5RS,8aSR)-5-(3-Chloro-phenylethynyl)-5-hydroxy-octahydro-quinolin-1-yl]-furan-2-yl-methanone
    9c: (±)-(4aRSs,5RS,8aSR)-5-(3-Chloro-phenylethynyl)-5-hydroxy-octahydro-quinoline-1-carboxylic acid tert-butyl ester
    9d: (±)-[(4aRS,5SR,8aSR)-5-(3-Chlora-phenyletynyl)-5-hydroxy-actahydro-quinolin-1-yl]-morpholin-4-yl-methanone
    9e: (±)-[(4aRS,5SR)-8aSR)-5-(3-chloro-phenylethynyl)-5-hydroxy-octahydro-quinolin-1-yl]-(4-methyl-piperazin-1-yl)-methanone
    10: (±4aRS,5RS,8a5R)-5-(3-chloro-phenylethynyl)-5-hydroxy-octahydro-quinoline-1-carboxylic acid ethyl ester and (±)-(4aRS,SSR,8aSR)-5-(3-chloro-phenylethynyl)-5-hydroxy-octahydro-quinoline-1-carboxylic acid ethyl ester
    10a: (±)-(4aRS,5SR,8aSR)-5-Hydroxy-5-m-tolylthynyl-octahydro-quinoline-1-carboxylic acid ethyl ester
    10b: (±)-(4aR5,5RS,8aSR)-5-Hydroxy-5-m-tolylethynyl-octahydro-quinoline-1-carboxylic acid ethyl ester
  3. A compound of claim 2 which is (-)-(3aR,4S,7aR)-4-Hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester.
  4. A process for the preparation of a compound according to claim 3 comprising the step of reacting 1-ethynyl-3-methyl-benzene and (-)-4-oxo-octahydro-indole-1-carboxylic acid tert-butyl ester and recovering the resulting compound in free base or add addition salt form.
  5. A compound of claim 2 or 3 in free base or pharmaceutically acceptable add addition salt form, for use as a pharmaceutical.
  6. A pharmaceutical composition comprising a compound of claim 1, 2 or 3 in free base or phamnaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent
  7. The use of a compound of claim 1, 2 or 3 in free base or pharmaceutically acceptable acid addition salt form, for the manufacture of a pharmaceutical composition designed for the treatment of disorders associated with irregularities of the glutamatergic signal transmission.
  8. The use of a compound of claim 1, 2 or 3 in free base or pharmaceutically acceptable acid addition salt form, for the manufacture of a pharmaceutical composition designed for the treatment of nervous system disorders mediated full or in part by mGluR5.
  9. The use of a compound of claim 1, 2 or 3 in free base or pharmaceutically acceptable acid addition salt form, for the manufacture of a pharmaceutical composition designed for the treatment of one or more disorder selected from the group consisting of epilepsy, cerebral ischemias, especially acute ischemias, ischemic diseases of the eye, muscle spasms such as local or general spasticity and, in particular, convulsions or pain.
  10. The use of a compound of claim 1, 2 or 3 in free base or pharmaceutically acceptable add addition salt form, for the manufacture of a pharmaceutical composition designed for the treatment of one or more disorder selected from the group consisting of Parkinson's disease, senile dementia, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis and multiple sclerosis, psychiatric diseases such as schizophrenia and anxiety, depression, pain, itch and drug abuse.
EP02792867A 2001-12-04 2002-12-03 Acetylene derivatives having mglur 5 antagonistic activity Expired - Lifetime EP1453512B8 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
SI200230385T SI1453512T1 (en) 2001-12-04 2002-12-03 Acetylene derivatives having mglur 5 antagonistic activity

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB0128996 2001-12-04
GBGB0128996.6A GB0128996D0 (en) 2001-12-04 2001-12-04 Organic compounds
PCT/EP2002/013670 WO2003047581A1 (en) 2001-12-04 2002-12-03 Acetylene derivatives having mglur 5 antagonistic activity

Publications (3)

Publication Number Publication Date
EP1453512A1 EP1453512A1 (en) 2004-09-08
EP1453512B1 true EP1453512B1 (en) 2006-05-31
EP1453512B8 EP1453512B8 (en) 2006-07-19

Family

ID=9926969

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02792867A Expired - Lifetime EP1453512B8 (en) 2001-12-04 2002-12-03 Acetylene derivatives having mglur 5 antagonistic activity

Country Status (32)

Country Link
US (4) US7348353B2 (en)
EP (1) EP1453512B8 (en)
JP (2) JP4176020B2 (en)
KR (2) KR100980901B1 (en)
CN (2) CN101366714B (en)
AR (2) AR037682A1 (en)
AT (1) ATE327755T1 (en)
AU (1) AU2002358585B2 (en)
BR (1) BR0214666A (en)
CA (1) CA2466560C (en)
CO (1) CO5590929A2 (en)
CY (1) CY1105460T1 (en)
DE (1) DE60211944T2 (en)
DK (1) DK1453512T3 (en)
EC (1) ECSP045139A (en)
EG (1) EG24936A (en)
ES (1) ES2263842T3 (en)
GB (1) GB0128996D0 (en)
HK (1) HK1071510A1 (en)
HU (1) HU229429B1 (en)
IL (1) IL161990A0 (en)
MX (1) MXPA04005456A (en)
MY (1) MY137774A (en)
NO (1) NO327005B1 (en)
NZ (1) NZ533266A (en)
PE (1) PE20030640A1 (en)
PL (1) PL212996B1 (en)
PT (1) PT1453512E (en)
RU (1) RU2341515C2 (en)
TW (1) TWI328578B (en)
WO (1) WO2003047581A1 (en)
ZA (1) ZA200403713B (en)

Families Citing this family (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0128996D0 (en) 2001-12-04 2002-01-23 Novartis Ag Organic compounds
US7772188B2 (en) 2003-01-28 2010-08-10 Ironwood Pharmaceuticals, Inc. Methods and compositions for the treatment of gastrointestinal disorders
GB0325956D0 (en) * 2003-11-06 2003-12-10 Addex Pharmaceuticals Sa Novel compounds
EP1734963A4 (en) 2004-04-02 2008-06-18 Merck & Co Inc Method of treating men with metabolic and anthropometric disorders
GB0503646D0 (en) * 2005-02-22 2005-03-30 Novartis Ag Organic compounds
GB0508319D0 (en) * 2005-04-25 2005-06-01 Novartis Ag Organic compounds
GB0508318D0 (en) * 2005-04-25 2005-06-01 Novartis Ag Organic compounds
GB0508314D0 (en) * 2005-04-25 2005-06-01 Novartis Ag Organic compounds
GB0514296D0 (en) * 2005-07-12 2005-08-17 Novartis Ag Organic compounds
EP2272509A1 (en) * 2006-09-11 2011-01-12 Novartis AG New Uses of metabotropic glutamate receptors
MX354786B (en) 2007-06-04 2018-03-21 Synergy Pharmaceuticals Inc AGONISTS OF GUANYLATE CYCLASE USEFUL FOR THE TREATMENT OF GASTROINTESTINAL DISORDERS, INFLAMMATION, CANCER and OTHER DISORDERS.
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
TW200924745A (en) * 2007-10-12 2009-06-16 Novartis Ag Organic compounds
AU2012254934B2 (en) * 2007-10-12 2013-10-17 Novartis Ag Metabotropic glutamate receptor modulators for the treatment of Parkinson's disease
CA2726917C (en) 2008-06-04 2018-06-26 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
CN102131503A (en) * 2008-06-30 2011-07-20 诺瓦提斯公司 Combination products comprising mGluR modulator for treating parkinson's disease
NZ590753A (en) 2008-08-12 2012-06-29 Novartis Ag Processes for the preparation of 4-oxo-octahydro-indole-1-carbocylic acid methyl ester and derivatives thereof
US8334287B2 (en) 2009-07-17 2012-12-18 Hoffmann-La Roche Inc. Imidazoles
US20120157464A1 (en) 2009-07-23 2012-06-21 Novartis Ag Use of azabicycloalkyl derivatives or pyrrolidine-2-one derivatives for the treatment or prevention of ataxia
TWI558398B (en) 2009-09-22 2016-11-21 諾華公司 Use of nicotinic acetylcholine receptor alpha 7 activators
WO2011048150A1 (en) 2009-10-20 2011-04-28 Novartis Ag Use of 1h-quinazoline-2,4-diones
MX2012012615A (en) * 2010-04-30 2012-12-17 Novartis Ag Predictive markers useful in the treatment of fragile x syndrome (fxs).
BR112012033290A2 (en) 2010-06-24 2016-11-22 Novartis Ag use of 1h-quinazoline-2,4-diones
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
WO2012084873A1 (en) 2010-12-20 2012-06-28 Novartis Ag 4- (hetero) aryl - ethynyl - octahydro - indole - 1 - carboxylic acid esters
EP2668159A1 (en) 2011-01-24 2013-12-04 Novartis AG 4-tolyl-ethynyl-octahydro-indole-1-ester derivatives
JP2014503568A (en) 2011-01-27 2014-02-13 ノバルティス アーゲー Use of nicotinic acetylcholine receptor α7 activator
CA2830458A1 (en) 2011-03-18 2012-09-27 Novartis Ag Combinations of alpha 7 nicotinic acetylcholine receptor activators and mglur5 antagonists for use in dopamine induced dyskinesia in parkinson's disease
EP2753331A1 (en) 2011-09-07 2014-07-16 Novartis AG Use of 1h-quinazoline- 2, 4 -diones for use in the prevention or treatment photosensitive epilepsy
WO2013131981A1 (en) 2012-03-08 2013-09-12 Novartis Ag Predictive markers useful in the diagnosis and treatment of fragile x syndrome (fxs)
GB201215033D0 (en) 2012-08-23 2012-10-10 Novartis Ag Diazepinone derivatives
BR112015016992A8 (en) 2013-01-15 2018-01-23 Novartis Ag use of nicotinic acetylcholine alpha 7 receptor agonists
WO2014111751A1 (en) 2013-01-15 2014-07-24 Novartis Ag Use of alpha 7 nicotinic receptor agonists for the treatment of narcolepsy
EP2970384A1 (en) 2013-03-15 2016-01-20 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
WO2014151200A2 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions useful for the treatment of gastrointestinal disorders
JP6606491B2 (en) 2013-06-05 2019-11-13 シナジー ファーマシューティカルズ インコーポレイテッド Ultra high purity agonist of guanylate cyclase C, method for producing and using the same
KR102290249B1 (en) * 2013-06-12 2021-08-17 노파르티스 아게 Modified release formulation
CN105669686B (en) * 2014-11-19 2018-08-03 上海合全药业股份有限公司 A kind of synthetic method of 6- (tertbutyloxycarbonyl) octahydros furans [2,3-c] Pyridine-4-carboxylic acid
AU2018310881C1 (en) 2017-07-31 2021-12-16 Novartis Ag Use of mavoglurant in the reduction of cocaine use or in preventing relapse into cocaine use
KR20200035262A (en) 2017-07-31 2020-04-02 노파르티스 아게 Use of mabogluant to reduce alcohol use or prevent alcohol recurrence
AU2020215849B2 (en) 2019-01-29 2023-07-27 Novartis Ag The use of an mGluR5 antagonist for treating opioid analgesic tolerance
EP4181918A2 (en) 2020-07-17 2023-05-24 Novartis AG Mavoglurant, a mglur5 antagonist, for use in the treatment in the reduction of opioid use
JP2023552833A (en) 2020-12-11 2023-12-19 ノバルティス アーゲー Use of mGluR5 antagonists for the treatment of amphetamine addiction
WO2022130136A1 (en) 2020-12-14 2022-06-23 Novartis Ag Use of mglur5 antagonists for treating gambling disorder

Family Cites Families (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2741009A1 (en) * 1976-09-22 1978-03-23 Sandoz Ag 4-STYRYL-4-INDOLINOL DERIVATIVES, THEIR USE AND PRODUCTION
DE2802833A1 (en) 1978-01-23 1979-07-26 Sandoz Ag 4-Styryl-4-indolinyl derivs. - used as hypolipaemics and antiarrhythmics to treat e.g. arteriosclerosis
US5264456A (en) 1989-12-29 1993-11-23 Allergan, Inc. Acetylenes disubstituted with a furyl group and a substituted phenyl group having retinoid like activity
US5284957A (en) 1992-09-03 1994-02-08 Eli Lilly And Company Excitatory amino acid receptor antagonists
US5593994A (en) 1994-09-29 1997-01-14 The Dupont Merck Pharmaceutical Company Prostaglandin synthase inhibitors
AU6709596A (en) 1995-08-22 1997-03-19 Japan Tobacco Inc. Amide compounds and use of the same
EP2223920A3 (en) 1996-06-19 2011-09-28 Aventis Pharma Limited Substituted azabicyclic compounds
TW544448B (en) * 1997-07-11 2003-08-01 Novartis Ag Pyridine derivatives
WO1999062869A1 (en) 1998-06-04 1999-12-09 Kumiai Chemical Industry Co., Ltd. Phenylacetylene derivatives and agricultural/horticultural bactericides
CN1187048C (en) 1998-10-02 2005-02-02 诺瓦提斯公司 MGluR 5 antagonists for treatment of pain and anxiety
IL146697A0 (en) 1999-07-06 2002-07-25 Lilly Co Eli SELECTIVE iGluR5 RECEPTOR FOR THE TREATMENT OF MIGRAINE
GB0007108D0 (en) 2000-03-23 2000-05-17 Novartis Ag Organic compounds
IL155202A0 (en) 2000-10-20 2003-11-23 Biocryst Pharm Inc Biaryl compounds as serine protease inhibitors
WO2002046166A1 (en) * 2000-12-04 2002-06-13 F. Hoffmann-La Roche Ag Phenylethenyl or phenylethinyl derivatives as glutamate receptor antagonists
GB0103045D0 (en) * 2001-02-07 2001-03-21 Novartis Ag Organic Compounds
US7138404B2 (en) 2001-05-23 2006-11-21 Hoffmann-La Roche Inc. 4-aminopyrimidine derivatives
GB0128996D0 (en) * 2001-12-04 2002-01-23 Novartis Ag Organic compounds
JP2005517640A (en) 2001-12-04 2005-06-16 エフ．ホフマン−ラ　ロシュ　アーゲー Substituted 2-amino-cycloalkanecarboxamides and their use as cysteine protease inhibitors
TW200303309A (en) 2001-12-04 2003-09-01 Bristol Myers Squibb Co Novel n-[4-(1h-imidazol-1-yl)-2-fluorophenyl]-3-trifluoromethyl)-1h-pyrazole-5-carboxamides as factor Xa inhibitors

Also Published As

Publication number Publication date
RU2341515C2 (en) 2008-12-20
CA2466560C (en) 2010-07-27
JP2005514381A (en) 2005-05-19
KR20050044657A (en) 2005-05-12
NZ533266A (en) 2005-02-25
CO5590929A2 (en) 2005-12-30
US20130331568A1 (en) 2013-12-12
CN101366714B (en) 2014-09-17
GB0128996D0 (en) 2002-01-23
IL161990A0 (en) 2005-11-20
PL212996B1 (en) 2012-12-31
US20120010263A1 (en) 2012-01-12
RU2004120781A (en) 2006-01-10
NO20042673L (en) 2004-06-25
ES2263842T3 (en) 2006-12-16
JP4176020B2 (en) 2008-11-05
NO327005B1 (en) 2009-04-06
AU2002358585B2 (en) 2006-01-19
DE60211944D1 (en) 2006-07-06
ATE327755T1 (en) 2006-06-15
JP2008303226A (en) 2008-12-18
EP1453512B8 (en) 2006-07-19
CY1105460T1 (en) 2010-04-28
HUP0402191A3 (en) 2010-03-29
EP1453512A1 (en) 2004-09-08
US20050065191A1 (en) 2005-03-24
HK1071510A1 (en) 2005-07-22
WO2003047581A1 (en) 2003-06-12
DK1453512T3 (en) 2006-08-28
DE60211944T2 (en) 2007-05-16
AU2002358585A1 (en) 2003-06-17
CA2466560A1 (en) 2003-06-12
CN1592623A (en) 2005-03-09
EG24936A (en) 2011-01-11
HU229429B1 (en) 2013-12-30
US20080146647A1 (en) 2008-06-19
TWI328578B (en) 2010-08-11
JP5036648B2 (en) 2012-09-26
MXPA04005456A (en) 2004-10-11
CN101366714A (en) 2009-02-18
MY137774A (en) 2009-03-31
PL368739A1 (en) 2005-04-04
PE20030640A1 (en) 2003-09-12
CN100430059C (en) 2008-11-05
KR100980901B1 (en) 2010-09-07
AR088921A2 (en) 2014-07-16
US8536229B2 (en) 2013-09-17
PT1453512E (en) 2006-10-31
US7348353B2 (en) 2008-03-25
ZA200403713B (en) 2005-10-26
KR100959204B1 (en) 2010-05-19
TW200304910A (en) 2003-10-16
BR0214666A (en) 2004-11-03
ECSP045139A (en) 2004-07-23
KR20100020044A (en) 2010-02-19
AR037682A1 (en) 2004-12-01
HUP0402191A2 (en) 2005-02-28

Similar Documents

Publication Publication Date Title
EP1453512B1 (en) Acetylene derivatives having mglur 5 antagonistic activity
WO2003084930A1 (en) Diphenylpyridine derivatives, the preparation thereof, and pharmaceutical compositions containing said derivatives
EA011087B1 (en) Compounds and pharmaceutical compositions for treating inflammation diseases
JP4465280B2 (en) Substituted dihydrophenanthridine sulfonamides
CA2112689A1 (en) Indoles
JPH10500106A (en) Substituted fused and bridged bicyclic compounds as therapeutics
US5641785A (en) Oxazoloquinolinone derivatives, their preparation and their therapeutic application as inhibitors of monoamine oxidase
JP2001518463A (en) Aminoalkylphenol derivatives and related compounds
FR2792635A1 (en) 2-Amino-cyclobutene-3,4-dione cyclohexane carboxamide derivatives are phosphodiesterase inhibitors useful for treating e.g. incontinence, dysmenorrhea, premature labor, sexual dysfunction, angina and asthma
CA2267247C (en) Heteroaryloxyethylamines as 5-ht1a ligands
JP3467072B2 (en) Preparation of lignan analogs
JPH10273464A (en) Substituted catechol derivative
WO2003106425A2 (en) Phenyl- and pyridyl-diazaheterocycles having a tnf-modulating activity

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20040705

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LI LU MC NL PT SE SI SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1071510

Country of ref document: HK

17Q First examination report despatched

Effective date: 20050624

RIN1 Information on inventor provided before grant (corrected)

Inventor name: AUBERSON, YVES

Inventor name: GASPARINI, FABRIZIO

Inventor name: HART, TERANCE W.

Inventor name: OFNER, SILVIO

Inventor name: ZIMMERMANN, KASPAR

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

RIN1 Information on inventor provided before grant (corrected)

Inventor name: GASPARINI, FABRIZIO

Inventor name: AUBERSON, YVES

Inventor name: HART, TERANCE W.

Inventor name: ZIMMERMANN, KASPAR

Inventor name: OFNER, SILVIO

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LI LU MC NL PT SE SI SK TR

AX Request for extension of the european patent

Extension state: RO

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

RAP2 Party data changed (patent owner data changed or rights of a patent transferred)

Owner name: NOVARTIS AG

Owner name: NOVARTIS PHARMA GMBH

REF Corresponds to:

Ref document number: 60211944

Country of ref document: DE

Date of ref document: 20060706

Kind code of ref document: P

RAP2 Party data changed (patent owner data changed or rights of a patent transferred)

Owner name: NOVARTIS PHARMA GMBH

Owner name: NOVARTIS AG

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

NLT2 Nl: modifications (of names), taken from the european patent patent bulletin

Owner name: NOVARTIS AG

Effective date: 20060719

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20060402515

Country of ref document: GR

REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Effective date: 20060817

ET Fr: translation filed
REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2263842

Country of ref document: ES

Kind code of ref document: T3

REG Reference to a national code

Ref country code: HK

Ref legal event code: GR

Ref document number: 1071510

Country of ref document: HK

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20061231

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20070301

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 14

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 15

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 16

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 20211124

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: TR

Payment date: 20211202

Year of fee payment: 20

Ref country code: SE

Payment date: 20211126

Year of fee payment: 20

Ref country code: SK

Payment date: 20211124

Year of fee payment: 20

Ref country code: PT

Payment date: 20211203

Year of fee payment: 20

Ref country code: CZ

Payment date: 20211125

Year of fee payment: 20

Ref country code: DE

Payment date: 20211116

Year of fee payment: 20

Ref country code: BG

Payment date: 20211208

Year of fee payment: 20

Ref country code: AT

Payment date: 20211129

Year of fee payment: 20

Ref country code: FI

Payment date: 20211209

Year of fee payment: 20

Ref country code: DK

Payment date: 20211209

Year of fee payment: 20

Ref country code: EE

Payment date: 20211129

Year of fee payment: 20

Ref country code: FR

Payment date: 20211125

Year of fee payment: 20

Ref country code: IE

Payment date: 20211123

Year of fee payment: 20

Ref country code: GB

Payment date: 20211118

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SI

Payment date: 20211123

Year of fee payment: 20

Ref country code: NL

Payment date: 20211203

Year of fee payment: 20

Ref country code: IT

Payment date: 20211129

Year of fee payment: 20

Ref country code: GR

Payment date: 20211129

Year of fee payment: 20

Ref country code: CH

Payment date: 20211126

Year of fee payment: 20

Ref country code: BE

Payment date: 20211203

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20220105

Year of fee payment: 20

Ref country code: CY

Payment date: 20211125

Year of fee payment: 20

REG Reference to a national code

Ref country code: DE

Ref legal event code: R071

Ref document number: 60211944

Country of ref document: DE

REG Reference to a national code

Ref country code: DK

Ref legal event code: EUP

Expiry date: 20221203

REG Reference to a national code

Ref country code: NL

Ref legal event code: MK

Effective date: 20221202

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: SK

Ref legal event code: MK4A

Ref document number: E 866

Country of ref document: SK

Expiry date: 20221203

REG Reference to a national code

Ref country code: GB

Ref legal event code: PE20

Expiry date: 20221202

REG Reference to a national code

Ref country code: BE

Ref legal event code: MK

Effective date: 20221203

REG Reference to a national code

Ref country code: FI

Ref legal event code: MAE

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK07

Ref document number: 327755

Country of ref document: AT

Kind code of ref document: T

Effective date: 20221203

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SK

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20221203

Ref country code: GB

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20221202

Ref country code: CZ

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20221203

REG Reference to a national code

Ref country code: SE

Ref legal event code: EUG

REG Reference to a national code

Ref country code: IE

Ref legal event code: MK9A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20221204

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20230427

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20221203

P01 Opt-out of the competence of the unified patent court (upc) registered

Effective date: 20230513

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20221204